Abstract
Guanylate binding proteins (GBPs) represent an evolutionary ancient protein family widely distributed among eukaryotes. They are interferon (IFN)-inducible guanosine triphosphatases that belong to the dynamin superfamily. GBPs are known to have a major role in the cell-autonomous innate immune response against bacterial, parasitic and viral infections and are also involved in inflammasome activation. Evolutionary studies depicted that GBPs present a pattern of gain and loss of genes in each family with several genes pseudogenized and some genes more divergent, indicative for the birth-and-death evolution process. Most species harbor large GBP gene clusters encoding multiple paralogs. Previous functional studies mainly focused on mouse and human GBPs, but more data are becoming available, broadening the understanding of this multifunctional protein family. In this review, we will provide new insights and give a broad overview about GBP evolution, conservation and their roles in all studied species, including plants, invertebrates and vertebrates, revealing how far the described features of GBPs can be transferred to other species.
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Introduction
GBPs are members of the dynamin superfamily (protein family) and the IFN-inducible guanosine triphosphatases. Of note, IFN inducibility is not true for GBPs in plants [1, 2] (Fig. 1a). The GBP proteins share common features and functions as outlined below:
Structure
The information on GBPs’ structure is scarce. Indeed, until now, out of seven human GBP paralogs (hGBP1-7) only structural data for human GBP1 (hGBP1) exist [3], which has been recently extended to hGBP2/5 [4]. GBPs comprise three main domains: the large GTPase (LG) domain at the N-terminus connected by a hinge region (N-terminal part in α6 and C-terminal part in α7) to the middle domain (MD) and the GTPase effector domain (GED) at the C-terminus (Fig. 1b). The LG domain is a globular domain including five motifs: P-loop (G1), switch I (G2), switch II (G3), (N/T) KxD motif (G4) and the guanine cap (G5). These motifs are involved in GTP binding/orientation, Mg2+ cofactor finding and GTP/GDP hydrolysis [2, 4, 5]. The MD is an α-helical elongated domain (α7-11) comprising two three-helix bundles (α9 is shared). The GED is an α-helical elongated domain (α12-13) which, in nucleotide free state, is folded onto LG and MD.
Dimerization and polymerization
Recently, it has been described that hGBPs probably share a conserved dimerization mode between paralogs [4]. Upon GTP binding and LG:LG interface building, the GBP structurally rearranges to an open state driven by GTPase hydrolysis cycles. Kinetically delayed, the MD domain rearranges beneath the LG domain of the second GBP. Hereby, the hinge regions cross each other and form a closed dimeric state, which is further stabilized by the MD interface (Fig. 1c) [4, 6,7,8,9]. For hGBP1, farnesylation and GTP-dependent polymerization have been observed, but the exact function remains unclear [9].
Based on current knowledge it may be hypothesized that the conserved closed dimeric state represents the actual “active” form of specific GBPs’ innate immunity-related functions but not all functions have to be solely related to dimerization [4].
Localization and membrane anchoring
hGBP1/2/5 harbor a CaaX motif at the C-terminus of the GED, which serves as a signal for in vivo isoprenylation (GBP1: farnesylated; GBP2/5: geranylgeranylated) and membrane anchoring. In a closed monomeric state hGBP1/2/5 localize homogenously distributed in the cytoplasm. Further, the isoprenyl moiety is buried in a hydrophobic pocket between GED (α12) and MD (α9) [2, 4, 5, 10]. Favored by the described GTP binding/hydrolysis and intra-dimeric interactions, the buried isoprenyl moiety is released from the hydrophobic pocket leading to a rearrangement into an open state. Subsequently, the released isoprenyl moiety is the determinant for membrane anchoring and, consequently, for the localization to the membranes at the cytosolic face of cellular compartments (Fig. 1d) (hGBP1: vesicle-like, plasma membrane; hGBP2: perinuclear membrane; hGBP5: Golgi). [4, 6, 8, 10]. Whereas the non-isoprenylated hGBP3/4 stay homogeneously localized in the cytosol or sometimes localized in the nucleus (Fig. 1d) [6, 11], hGBP4/6 can also be found to colocalize with vesicle-like structures without being isoprenylated [12]. It has also been described that homo- and heterodimerization influence localization [6, 11] but details are not yet clear.
GBP functions and roles in innate immunity
The expression of GBPs is triggered by inflammatory signals. The most potent stimuli for expression are interferons (IFN) due to IFN-stimulated response elements in the 5′ cis regulatory region of the hGBP genes. GBPs are among the most upregulated genes upon IFNγ stimulation. Especially hGBP1/5 expression is upregulated by up to two to three orders of magnitudes [13]. GBPs can be further stimulated by interleukins (ILs) and tumor necrosis factors (TNFs), but to a much lesser extent (reviewed in [13]).
The IFN-inducibility hints to some functions of GBPs. They are part of the cell-autonomous innate immune response against various pathogens and, in this context, are involved in canonical and non-canonical inflammasome activation. They respond to various intracellular bacteria, mostly gram negative, but also gram positive, as well as parasites (e.g., Shigella flexneri, Salmonella enterica, Salmonella typhimurium, Legionella pneumophila, Francisella novicida, Chlamydia trachomatis, Listeria monocytogenes, Mycobacterium bovis, Leishmania donovani and Toxoplasma gondii) (reviewed in [13, 14]). Moreover, GBPs inhibit viral infections such as vesicular stomatitis virus (VSV), classical swine fever virus (CSFV), murine norovirus-1 (MNV-1), Newcastle disease virus (NDV), encephalomyocarditis virus (EMCV), dengue virus (DENV), herpes simplex virus type 1 (HSV-1), Kaposi’s sarcoma-associated herpesvirus (KSHV), hepatitis E virus (HEV), hepatitis C virus (HCV), influenza A virus (IAV), human immunodeficiency virus (HIV) and respiratory syncytial virus (RSV) (Fig. 1e) (reviewed in [14, 15]).
Taken together, GBPs have been considered as major players in the host innate immunity by providing defense against a broad range of invading pathogens.
GBP evolution and conservation
The origin and evolution of GBPs have been analyzed only recently with most of the evolutionary history of GBPs still unclear [16,17,18,19]. GBPs originated from a common ancestor and belong to the multigene family of the large dynamin superfamily [20]. GBPs can be found in a broad range of organisms from plants to humans [18]. The presence of GBPs in plants species like Arabidopsis thaliana, Oryza sativa and Solanum lycopersicum indicates that GBPs are active in organisms that do not present migratory immune cells and an IFN-inducible immune system [18].
In mammals, GBP genes are usually organized in tandem on the same chromosome [19, 20]; however, in some rodents, like Mus and Rattus norvegicus, the Gbps are located on two gene clusters on different chromosomes [16]. In addition, in zebrafish and frogs, gbp genes are found in three small genomic islands [13]. Plants also have a variation regarding the number of GBPL (GBP-like) genes present in their genome, for example, Oryza sativa has three orthologs, while in Arabidopsis thaliana and Zea mays seven GBPL are encoded in their genome [18]. Altogether, this suggests that independent duplication events contributed to GBP diversity across plant and animal kingdoms [18]. Moreover, since GBPs are a multigene family that belongs to the immune system, it follows the birth-and-death process of evolution [21]. This results in some genes being either deleted or maintained in the genome. When maintained, the genes can acquire a new function (neofunctionalization), split functions (subfunctionalization) or even lose function and become pseudogenes [17, 22]. For example, GBP3 gene appears to have emerged only in Simiiformes through a duplication of GBP1 and gained a new function being responsible for the regulation of caspase-4 activation (Table 1) [23]. As for GBP7, it most likely emerged from a duplication event of GBP4 and seems to be only present in primates (Table 1) [17].
GBP4 and GBP5 seem to have been deleted from the genomes of Old-World monkeys and the lack of GBP5 orthologs might explain the HIV-2 transmission susceptibility in these primates since GBP5 inhibits HIV-2 infection [13, 17].
Some GBP orthologs are not present in different species, while others might be exclusive to specific orders. According to phylogenetic analyses it appears that primate GBP1, GBP3 and GBP7 are absent from muroid genomes (Table 1) [16]. This further indicates that the nomenclature of muroids Gbps has been incorrect and functional studies of these Gbps might have led to misleading results [16]. Following an evolutionary study in muroids, Gbp2, Gbp5 and Gbp6 have been found to be orthologs to their primate counterparts [16].
Gbp2 is found in every family of muroids and duplication events occurred in all genera except in Rattus. Gbp5 presents only one copy in each species of muroids, similar to primates. Maintenance of Gbp2 and Gbp5 in the muroid genomes supports the importance of these two genes for the host immune system [24, 25].
Phylogenetic analyses in Muroidea and Cricetidae indicate the presence of four Gbps that are exclusive to these taxa (Gbpa, b, c and d) (Table 1) [16]. The Gbpa and Gbpb groups are mainly composed of Gbps previously classified in public databases (NCBI and Ensembl) as Gbp1 [16]. Phylogenetically, they are not similar to hGBP1. Interestingly, these genes are not present in Mus musculus [16]. The function of these genes has yet to be determined, but the study of the sequences and the 3D structure of the proteins may provide hints on their function. Gbpc is only present in three species, being absent in Mus musculus, but its function is also not known. Considering the Gbpd group, three main groups emerged and are present in all species of muroids indicating a possible duplication in the common ancestor of Muridae and Cricetidae (Table 1) [16]. The Mus musculus classified as Gbpd1 [16], previously annotated in NCBI and Ensembl as Gbp7, appears to be a cellular host dependency factor for IAV replication [26].
Gbp6 cluster is present in most Muridae and Cricetidae species, and in Mus musculus and M. caroli, an expansion of this gene has observed, with Mus musculus presenting six copies and Mus caroli four. This expansion might be explained as a compensation mechanism due to the lack of Gbpa, b and c in these two species [16].
The evolutionary history of the GBP multigene family is complex and dynamic with duplication (Gbp2 and Gbp6 in several species), deletion (Gbpa, b and c in Mus musculus; Table 1) and neofunctionalization (GBP3 in primates) of genes, in line with the proposed birth-and-death mode of evolution [17]. In each mammalian family, the different evolutionary histories open new research opportunities to study the evolution and function of GBPs, which should be conducted in a more holistic approach.
GBP functions in plants, invertebrates and vertebrates
GBPs in plants
GBP-like proteins seem to be widely distributed as they even exist in plants. Plants solely rely on innate immune mechanisms to resist against phytopathogens (reviewed in [27, 28]). GBPs are poorly characterized in plants, but first results have been obtained in recent years. Indeed, tomato (Solanum lycopersicum) GBP homolog, SIGBP1, has been reported to be involved in fruit tissue differentiation by maintaining cells in a non-proliferative state [29] (Fig. 2A). First comparisons of the modeled structure of Arabidopsis GBP-like (AtGBPL) to hGBP1 crystal structure revealed a similar architecture. AtGBPL1/3 seem to comprise an intrinsically disordered region (IDR) at the C-terminus instead of an isoprenylation motif [18]. Functional studies with AtGBPL1/2/3 have revealed the roles of AtGBP1 (negative allosteric regulator of AtGBP3) and AtGBP3 in host defense. Indeed, they confer resistance to phytopatogens such as Pseudomonas syringae pv. maculicola (Psm), Pseudomonas syringae pv. Tomato (Pst) and Hyaloperonospora arabidopsidis (Hpa). Upon salicylic acid, pipecolic acid or phytopathogen activation, AtGBP3 condensates to unique membraneless organelles, termed GBPL defense-activated condensates (GDACs), within the nucleus, binding defense-gene promotors and recruiting transcriptional coactivators. This, in turn, reprograms the host gene expression to promote host defense responses (Fig. 2a). GDACs have also been observed in tomato and maize, which could hint for a conserved mechanism in plants [15]. Since phytohormone salicylic acid biosynthesis is also promoted by plant viruses (reviewed in [30]), it seems possible that AtGBPLs also might be involved in antiviral response, but this hypothesis needs to be proven.
In summary, GBP-dependent innate immunity processes are present in plants and animals and, thus, probably exist already over a longer period of time.
GBPs in invertebrates
The function/presence of GBPs in invertebrates is still unclear. Indeed, in silico analyses have revealed that non-vertebrate species harbor GBP-like genes, but not all of them seem to be completely lacking them [13, 20]. If this is due to a low genome coverage or, in fact, if these genes are not present still needs further clarification. In amphioxus (Branchiostoma japonicum), expression of GBPs is upregulated in immune-related tissues [20] (Fig. 2b), which could indicate their involvement in innate host defense.
Recently, the BmAtlastin-n protein of silkworm (Bombyx mori) has been suggested to be part of the GBP family [31] due to the lack of the typical atlasin transmembrane domain [32] and similarity in the GTPase domain [31]. Transgenic silk worms overexpressing BmAtlastin-n have shown in vitro and in vivo inhibition of viral reproduction capacity of Bombyx mori nucleopolyhedrovirus (BmNPV), a virus causing nuclear polyhedrosis [32]. The mechanism of viral inhibition is elusive, but it seems to correlate with the reduction of VP39 (capsid protein from late baculovirus gene) expression levels (mRNA and protein) [32]. Furthermore, it also enhances in vivo resistance against the obligate intracellular parasite microsporidia. Therefore, BmAtlastin-n seems to protect from intracellular infections caused by more than one pathogen (Fig. 2b), similar to other GBPs.
Why some invertebrates harbor GBPs in their genome and others seem to have lost them remains an open question requiring further investigations. Since atlastins and GBPs are closely related, it raises the question if in invertebrates without GBP homologs atlastins may have adopted some of their defense functions or if their common ancestor already possessed anti-pathogenic functions.
Gbps in teleosts
Studies regarding Gbps in teleosts are scarce. The first characterization of Gbps in fish has been in 2006 by Robertsen and colleagues [33], while mammalian GBPs have been described since 1983 [34]. The Gbp found in rainbow trouts (rbtGBP) appears to have a similar structure as hGBP1 with similar domains and a CaaX motif at the C-terminus, responsible for isoprenylation. Moreover, the most conserved region is the N-terminal surrounding GTP-binding region (amino acid 6–278) [33], while the C-terminal region is 43 amino acids longer compared to the human counterpart [33]. rbtGbp shares 41 to 47% amino acid sequence identity with mammalian GBPs. Interestingly, the region encompassing the GTP-binding motifs shares 67% identity with mammals. However, the C-terminus has only 37% identity with the mammalian GBPs [33]. The transcription level of rbtGBP is upregulated by lipopolysaccharide (LPS) and polyinosinic polycytidylic acid (poly I:C, double-stranded RNA analog) [43] (Fig. 2c). This may hint for an involvement of rbtGBP in innate immunity against bacteria and RNA viruses. Zebrafish Gbp is similar in length to the rbtGbp, but lacks a CaaX motif at the end of the C-terminus [33]. Nevertheless, DrGbp may play a role in the innate immunity against bacterial infections since DrGbp4 is involved in inflammasome activation and clearance of Salmonella typhimurium (St) infections [35].
In Danio rerio, eight Gbps have been found, with two Gbps being studied until now, Gbp1 and Gbp4. The nomenclature of gbps in fish is probably inaccurate since they do not cluster with their human counterparts, similar to the observations in muroids [26]. DrGbp1 contains an N-terminal GTPase domain and a helical C-terminal domain similar to mammalian GBPs [36]. DrGbp4 has a similar architecture as DrGBP1 with an additional C-terminal caspase recognition domain (CARD) and shares 53% identity with hGBP5 [35]. DrGbp4 is an IFNγ-induced GTPase, similar to mammalian GBPs. It is expressed in neutrophils, but in macrophages expression levels were hardly detected [35]. Tyrkalska and colleagues have demonstrated the paramount role of Gbp4 in bacterial clearance, being crucial for the biosynthesis of prostaglandins via an inflammasome-dependent pathway to clear St bacterial infection [35]. The GTPase activity of Gbp4 is crucial for caspase-1 activity, inflammasome activation and resistance to infection by St bacterial infection [35]. Indeed, Gbp4-deficient fish have a negatively affected caspase-1 activity and display increased susceptibility to St infections compared to fish with wildtype Gbp4. Interestingly, when Gbp4-deficient fish are trans-complemented with mouse Gbp5, St susceptibility decreases and caspase-1 defects are rescued [35]. Additionally, DrGbp4 regulates the expression of WD repeat domain 90 (WDR90), which is a component of the NOD-like receptor with CARD domain 4 inflammasome and is responsible for the conformational change needed for its activation [37] (Fig. 2c). Altogether, in fish, Gbps appear to have also an important role in the innate immune system, especially for bacterial infection. However, more studies are needed to further understand the functions of Gbps in teleost.
GBPs in mammals
Several studies have already been performed to understand the functions of GBPs in humans and, at some extent, in rodents and few further mammals; however, in general, the function of the majority of the mammalian GBPs remains unclear.
Since we would like to emphasize in this review the roles of non-human GBPs, we only shortly point out the antiviral activity of hGBPs. Needless to say their activity against bacteria and parasites are not less important, they have been recently reviewed in detail in [13, 14]. hGBP1/2/3/5 are known to be involved in restriction of viruses, employing thereby various mechanisms and targeting different steps in their life cycle. Yet, the underlying mechanisms remain elusive for specific viruses [14, 15]. hGBP1 employs several mechanisms to restrict viruses (Fig. 3a). For KSHV, the transport of the viral capsid to the nucleus is hampered by disruption of the actin filaments by hGBP1 [38]. HEV is inhibited through the relocation of the capsid protein by hGBP1 to the lysosome [39]. For HCV, the observed interaction with RNA-dependent RNA polymerase NS5B could be a possible explanation for the viral restriction [40]. In the case of IAV, the NS1 virulence factor is antagonized by hGBP1 [41]. For other viruses (e.g., VSV, DENV) the mode of action for their inhibition by GBP1 remains unknown [42, 43]. hGBP1 may employ similar mechanisms as mentioned above to inhibit the other viruses but also other mechanisms are conceivable. hGBP3 has only now been identified to play a role in IAV infection by inhibiting the viral polymerase complex [44] (Fig. 3b). GBP2/5 interfere with the host protease furin, which impairs HIV glycoprotein maturation resulting in a decreased infectivity of released viral particles [12, 45]. This has been also observed for Zika virus (ZIKV), measles virus (MEV) and lentiviral particles pseudotyped with various envelope glycoproteins (avian IAV, murine leukemia virus (MLV), Marburg virus (MARV) and human endogenous retrovirus K (HERV-K)) [12, 45, 46]. GBP5 further restricts the replication of RSV by reducing intracellular levels of the viral small hydrophobic protein [47]. Thus, GBP5 is generally involved in innate immunity as it can induce enhanced production of IFN and proinflammatory signals [48] (Fig. 3c).
Five pig (p) GBPs are described in literature. Based on NCBI, Sus scrofa has 7 GBPs in one gene cluster on chromosome 4 (accession numbers: NM_001128473.1, NM_001128474.1, XM_005663706.3, XM_021090310.1, XM_013997408.2, XM_021090315.1, XM_005663708.3). Only pGBP1/2 have been characterized on protein level. They share a conserved N-terminal GTPase domain and a C-terminal CaaX motive similar to other mammalian GBPs [49]. Pig GBP research is limited to pathogens especially affecting the global swine industry: the respiratory syndrome virus (PRRSV) and classical swine fever virus (CSFV) [50]. CSFV replication is potently inhibited by pGBP1 via its GTPase activity. pGBP1 mainly acts in the early phase of viral replication by inhibiting the translation efficiency of the internal ribosome entry site (IRES). Notably, CSFV NS5A protein counteracts pGBP1’s antiviral activity by inhibition of the GTPase activity [50]. For PRRSV, a quantitative trait locus (QTL) on Sus scrofa chromosome (SSC) 4 has been identified being beneficial for controlling infection. The characterization of this QTL revealed that it contains inter alia pGBP1/2/4/5/6 and that the QTL is associated with resistance to PRRSV infection. Furthermore, pGBP1/5/6 lead to a reduction of PRRSV viral loads in vivo in pigs [51,52,53,54]. Yet, the underlying mechanisms remain elusive.
Tupaia has 5 copies of GBPs in one gene cluster similar to humans, while most rodents present two gene clusters [19, 55]. Also similar to human and mouse GBPs, the coding region of Tupaia GBPs (tGBPs) ranges from 1733 to 1884 bp and the molecular weight of the proteins is between 67 to 72kD [55]. Most of the conserved motifs are present, particularly in the N-terminus where the GTPase domain is located. As expected, the C-terminus shares low sequence identity among the different groups. Phylogenetically, the sequences of tGBP genes are clustered with the hGBP genes, which indicates that the Tupaia genes are human orthologs [55]. Only in tGBP1, tGBP2 and tGBP5 a CaaX motif is present as in humans and mice [13, 56, 57]. This motif allows isoprenylation and consequently the anchorage to membranous organelles, enabling the destruction of pathogen-containing vacuoles, mainly bacterial pathogens, which exposes the pathogen to the host [15, 58,59,60].
When acute signaling is absent, hGBPs are expressed at low to medium levels in immune cells, lung, liver, kidney, brain and skin [13, 61]. tGBPs are also ubiquitously expressed at low levels in heart, spleen, kidneys, intestines, liver, lung and brain [55]. Human, mouse and Tupaia GBPs are strongly induced by IFN [19, 55, 62, 63] and Tupaia mRNA levels of GBPs are increased after RNA virus infections of primary renal cells such as Newcastle disease virus (NDV) and encephalomyocarditis virus (EMCV), and DNA virus type 1 herpes simplex virus (HSV-1) [55] (Fig. 4b).
As outlined above, hGBP1 is the most studied GBP, it has been described to have antiviral activity against a broad range of viruses [38, 40, 42, 64]. In Tupaia, tGBP1 is the only GBP from the five tGBPs that displays antiviral activity against VSV and HSV-1. It significantly represses the primary transcription of VSV viral genomes, but only presents a rather moderate effect against HSV-1 [55]. For VSV-G, tGBP1 restricts the viral genomic transcription in the cytoplasm by competitively binding to the VSV-N subunit [55]. The moderate HSV-1 inhibition by tGBP1 is tSTING-dependent, promoting tSTING-mediated autophagy, but the mechanism remains unclear. The authors speculated that autophagy could clear pathogens and DNA from the cytoplasm [65].
All tGBPs are upregulated through different viral infections, which suggests they may play a role in antiviral immunity (Fig. 4B). Yet, it is unclear how they inhibit viral replication, infectivity and proliferation [55]. The other four tGBPs need to be further investigated as Tupaia is becoming a recognized animal model to study human diseases (e.g., metabolic, brain aging, neurological, psychiatric and cancer) due to its closer relationship to humans than rodents [55] and also to its susceptibility to a wide range of human pathogens (HCV, HSV and SARS-CoV-2) [55, 64, 66, 67].
Murine GBP functions are the second most studied after human GBPs. As previously described, they are important for the host defense against pathogens and inflammasome activation. mGBP2 antiviral activity has been first described in 2005, revealing inhibition of VSV and EMCV replication [68]. EMCV replication inhibition requires GTPase activity of mGBP2, unlike the inhibition of VSV replication [68]. Murine norovirus (MNV) replication is inhibited when mGBP2 is expressed in mouse macrophages. The N-terminus of mGBP2 is crucial for anti-MNV activity since only GBP2 mutants that express the G domain and the GM domain inhibit viral replication at RNA and protein level, M domain alone and the remaining domains did not present anti-MNV activities [69]. hGBP2 and hGBP5 have been described to exert a broad antiviral activity against Zika virus, measles, HIV-1 and influenza A virus by reducing their replication and also impairing furin-mediated processing of envelope glycoproteins leading to a decrease in infectivity [12, 45]. Despite the phylogenetic analyses and the conserved function of GBPs, the antiviral functions of mGBP2 and mGBP5 are yet to be fully disclosed and further studies are needed.
Additional studies demonstrate that mGbp2 knockout increases susceptibility to infections with Toxoplasma gondii and Francisella novicida; yet mGBP2 did protect against infections with Listeria monocytogenes [24, 70]. mGBP5 also provides host defense against bacterial infections such as L. monocytogenes and F. novicida [24, 25]. In mouse macrophages, mGBP5 mediates caspase-11 activation and pyroptosis upon Bacillus abortus infection; knockdown of mGbp5 decreased IL-1β concentrations and, expectedly, bacterial count in macrophages is increased [71, 72].
For the newly classified Gbp6, previously designated Gbp4 in Mus musculus [16], Wandel and colleagues demonstrated its importance in caspase-4 recruitment, with the depletion of Gbp4 in cells leading to the inability of processing and releasing IL-18 during Shigella flexneri and Salmonella typhimurium infection [23], confirming that GBPs are crucial for inflammasome activation and bacterial clearance. Most studies have focused on the individual function of each mGBP; however, the combined function of GBPs is starting to be addressed. Indeed, en bloc knockout of mGBPs located on chromosome 3 leads to reduced release of IL-18 and IL-1β via canonical NLRP3 and AIM2 inflammasomes, which is needed for IFN-γ production and host defense against bacteria, ultimately increasing susceptibility of infection [24, 73]. Moreover, it has been described that mGBP1, mGBP6, mGBP7 and mGBP10 are paramount to hamper virulent strains of L. monocytogenes and M. bovis in mouse involving phagocyte oxidase, antimicrobial peptides and autophagy effectors [63]. Silencing mGbps with siRNAs has indicated that the protective effects of mGBPs operate in a collaborative way, since the combination of siRNAs decreased the killing ability via IFN-γ [63] (Fig. 4c).
Curiously, the expression of all Gbps located on chromosome 3 have displayed a beneficial interaction which limited acute inflammatory bone loss since GbpChr3−/− mouse cells exhibit increased bone loss compared to wildtype [74].
Concluding remarks
GBPs exist in a variety of eukaryotic organisms ranging from plants to animal kingdoms. Despite playing an important role in the innate immunity, the evolutionary history of GBPs as a multigene family is not yet fully disclosed. The immune system is continuously challenged by a broad range of intracellular pathogens, which leads to a complex evolution of the innate immunity genes. In each family, the number of GBPs varies, presenting several events of duplication, pseudogenization and deletion. Human and mouse GBPs have been characterized in more detail, but mostly restricted to GBPs 1/2/5. Yet, even for those, many functions remain undetermined as GBPs seem to be involved in a complicated cellular network. In this review, we provide insights on the maintenance of GBPs basal functions, like resistance to pathogens (viral, bacterial and parasitic); however, the detailed mechanisms and networks among species have not yet been sufficiently characterized. Therefore, studies on GBPs including more species may be beneficial to further understand the complex GBP network and their functions. It will be also crucial to understand the differences within the GBP gene clusters even in closely related species.
References
MacMicking JD (2004) GTP-binding proteins: structure-function relationships. Trends Immunol 25(11):601–609. https://doi.org/10.1016/j.it.2004.08.010
Jimah JR, Hinshaw JE (2019) Structural insights into the mechanism of dynamin superfamily proteins. Trends Cell Biol 29(3):257–273. https://doi.org/10.1016/j.tcb.2018.11.003
Prakash B, Praefcke GJK, Renault L, Wittinghofer A, Herrmann C (2000) Structure of human guanylate-binding protein 1 representing a unique class of GTP-binding proteins. Nature 403(6769):567–571. https://doi.org/10.1038/35000617
Cui W, Braun E, Wang W, Tang J, Zheng Y, Slater B et al (2021) Structural basis for GTP-induced dimerization and antiviral function of guanylate-binding proteins. Proc Natl Acad Sci USA 118(15):1–9. https://doi.org/10.1073/pnas.2022269118
Wittinghofer A, Vetter IR (2011) Structure-function relationships of the G domain, a canonical switch motif. Annu Rev Biochem 80:943–971. https://doi.org/10.1146/annurev-biochem-062708-134043 (Epub 2011/06/17)
Britzen-Laurent N, Bauer M, Berton V, Fischer N, Syguda A, Reipschläger S et al (2010) Intracellular trafficking of guanylate-binding proteins is regulated by heterodimerization in a hierarchical manner. PLoS ONE 5(12):e14246. https://doi.org/10.1371/journal.pone.0014246
Shydlovskyi S, Zienert AY, Ince S, Dovengerds C, Hohendahl A, Dargazanli JM et al (2017) Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein. Proc Natl Acad Sci USA 114(28):E5559–E5568. https://doi.org/10.1073/pnas.1620959114
Sistemich L, Dimitrov Stanchev L, Kutsch M, Roux A, Günther Pomorski T, Herrmann C (2021) Structural requirements for membrane binding of human guanylate-binding protein 1. FEBS J 288(13):4098–4114. https://doi.org/10.1111/febs.15703
Sistemich L, Kutsch M, Hämisch B, Zhang P, Shydlovskyi S, Britzen-Laurent N et al (2020) The molecular mechanism of polymer formation of farnesylated human guanylate-binding protein 1. J Mol Biol 432(7):2164–2185. https://doi.org/10.1016/j.jmb.2020.02.009
Ji C, Du S, Li P, Zhu Q, Yang X, Long C et al (2019) Structural mechanism for guanylate-binding proteins (GBPs) targeting by the Shigella E3 ligase IpaH9.8. Plos Pathog 15(6):e1007876. https://doi.org/10.1371/journal.ppat.1007876
Tripal P, Bauer M, Naschberger E, Mörtinger T, Hohenadl C, Cornali E et al (2007) Unique features of different members of the human guanylate-binding protein family. J Interferon Cytokine Res 27(1):44–52. https://doi.org/10.1089/jir.2007.0086
Braun E, Hotter D, Koepke L, Zech F, Groß R, Sparrer KMJ et al (2019) Guanylate-binding proteins 2 and 5 exert broad antiviral activity by inhibiting furin-mediated processing of viral envelope proteins. Cell Rep 27(7):2092–104.e10. https://doi.org/10.1016/j.celrep.2019.04.063
Tretina K, Park E-S, Maminska A, MacMicking JD (2019) Interferon-induced guanylate-binding proteins: guardians of host defense in health and disease. J Exp Med 216(3):482–500
Kutsch M, Coers J (2020) Human guanylate binding proteins: nanomachines orchestrating host defense. FEBS J. https://doi.org/10.1111/febs.15662
Zhang R, Li Z, Tang Y-D, Su C, Zheng C (2021) When human guanylate-binding proteins meet viral infections. J Biomed Sci 28(1):17. https://doi.org/10.1186/s12929-021-00716-8
Côrte-Real JV, Baldauf H-M, Melo-Ferreira J, Abrantes J, Esteves PJ (2022) Evolution of guanylate binding protein (GBP) genes in muroid rodents (Muridae and Cricetidae) reveals an outstanding pattern of gain and loss. Front Immunol. https://doi.org/10.3389/fimmu.2022.752186
Côrte-Real JV, Baldauf HM, Abrantes J, Esteves PJ (2021) Evolution of the guanylate binding protein (GBP) genes: emergence of GBP7 genes in primates and further acquisition of a unique GBP3 gene in simians. Mol Immunol 132:79–81. https://doi.org/10.1016/j.molimm.2021.01.025 (Epub 2021/02/08)
Huang S, Meng Q, Maminska A, MacMicking JD (2019) Cell-autonomous immunity by IFN-induced GBPs in animals and plants. Curr Opin Immunol 60:71–80. https://doi.org/10.1016/j.coi.2019.04.017 (Epub 2019/06/09)
Olszewski MA, Gray J, Vestal DJ (2006) In silico genomic analysis of the human and murine guanylate-binding protein (GBP) gene clusters. J Interferon Cytokine Res 26(5):328–352. https://doi.org/10.1089/jir.2006.26.328 (Epub 2006/05/13)
Li G, Zhang J, Sun Y, Wang H, Wang Y (2009) The evolutionarily dynamic IFN-inducible GTPase proteins play conserved immune functions in vertebrates and cephalochordates. Mol Biol Evol 26(7):1619–1630. https://doi.org/10.1093/molbev/msp074 (Epub 2009/04/17)
Nei M, Gu X, Sitnikova T (1997) Evolution by the birth-and-death process in multigene families of the vertebrate immune system. Proc Natl Acad Sci 94(15):7799–7806. https://doi.org/10.1073/pnas.94.15.7799
Nei M, Rooney AP (2005) Concerted and birth-and-death evolution of multigene families. Annu Rev Genet 39:121–152. https://doi.org/10.1146/annurev.genet.39.073003.112240
Wandel MP, Kim B-H, Park E-S, Boyle KB, Nayak K, Lagrange B et al (2020) Guanylate-binding proteins convert cytosolic bacteria into caspase-4 signaling platforms. Nat Immunol. https://doi.org/10.1038/s41590-020-0697-2
Meunier E, Wallet P, Dreier RF, Costanzo S, Anton L, Rühl S et al (2015) Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida. Nat Immunol 16(5):476–484. https://doi.org/10.1038/ni.3119 (Epub 2015/03/17)
Shenoy AR, Wellington DA, Kumar P, Kassa H, Booth CJ, Cresswell P et al (2012) GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals. Science 336(6080):481–485. https://doi.org/10.1126/science.1217141 (Epub 2012/03/31)
Feng M, Zhang Q, Wu W, Chen L, Gu S, Ye Y et al (2021) Inducible guanylate-binding protein 7 facilitates influenza A virus replication by suppressing innate immunity via NF-κB and JAK-STAT signaling pathways. J Virol 95(6):e02038-e2120. https://doi.org/10.1128/JVI.02038-20
Bentham AR, De la Concepcion JC, Mukhi N, Zdrzałek R, Draeger M, Gorenkin D et al (2020) A molecular roadmap to the plant immune system. J Biol Chem 295(44):14916–14935. https://doi.org/10.1074/jbc.REV120.010852 (Epub 2020/08/21)
Dangl JL, Horvath DM, Staskawicz BJ (2013) Pivoting the plant immune system from dissection to deployment. Science 341(6147):746–751. https://doi.org/10.1126/science.1236011 (Epub 2013/08/21)
Musseau C, Jorly J, Gadin S, Sørensen I, Deborde C, Bernillon S et al (2020) The tomato guanylate-binding protein SlGBP1 enables fruit tissue differentiation by maintaining endopolyploid cells in a non-proliferative state. Plant Cell 32(10):3188–3205. https://doi.org/10.1105/tpc.20.00245
Murphy AM, Zhou T, Carr JP (2020) An update on salicylic acid biosynthesis, its induction and potential exploitation by plant viruses. Curr Opin Virol 42:8–17. https://doi.org/10.1016/j.coviro.2020.02.008 (Epub 2020/04/25)
Dong Z, Zheng N, Hu C, Huang X, Chen P, Wu Q et al (2021) Genetic bioengineering of overexpressed guanylate binding protein family BmAtlastin-n enhances silkworm resistance to Nosema bombycis. Int J Biol Macromol 172:223–230. https://doi.org/10.1016/j.ijbiomac.2021.01.021 (Epub 2021/01/17)
Liu T-h, Dong X-l, Pan C-x, Du G-y, Wu Y-f, Yang J-g et al (2016) A newly discovered member of the Atlastin family, BmAtlastin-n, has an antiviral effect against BmNPV in Bombyx mori. Sci Rep 6(1):28946. https://doi.org/10.1038/srep28946
Robertsen B, Zou J, Secombes C, Leong J-A (2006) Molecular and expression analysis of an interferon-gamma-inducible guanylate-binding protein from rainbow trout (Oncorhynchus mykiss). Dev Comp Immunol 30(11):1023–1033. https://doi.org/10.1016/j.dci.2006.01.003
Cheng YS, Colonno RJ, Yin FH (1983) Interferon induction of fibroblast proteins with guanylate binding activity. J Biol Chem 258(12):7746–7750 (Epub 1983/06/25)
Tyrkalska SD, Candel S, Angosto D, Gómez-Abellán V, Martín-Sánchez F, García-Moreno D et al (2016) Neutrophils mediate Salmonella Typhimurium clearance through the GBP4 inflammasome-dependent production of prostaglandins. Nat Commun 7:12077. https://doi.org/10.1038/ncomms12077 (Epub 2016/07/02)
Jin T, Huang M, Smith P, Jiang J, Xiao TS (2013) Structure of the caspase-recruitment domain from a zebrafish guanylate-binding protein. Acta Crystallogr Sect F Struct Biol Cryst Commun 69(Pt 8):855–860. https://doi.org/10.1107/S1744309113015558 (Epub 2013/07/27)
Valera-Pérez A, Tyrkalska SD, Viana C, Rojas-Fernández A, Pelegrín P, García-Moreno D et al (2019) WDR90 is a new component of the NLRC4 inflammasome involved in Salmonella Typhimurium resistance. Dev Comp Immunol 100:103428. https://doi.org/10.1016/j.dci.2019.103428
Zou Z, Meng Z, Ma C, Liang D, Sun R, Lan K (2017) Guanylate-binding protein 1 inhibits nuclear delivery of Kaposi’s sarcoma-associated herpesvirus virions by disrupting formation of actin filament. J Virol 91(16):e00632-e717
Glitscher M, Himmelsbach K, Woytinek K, Schollmeier A, Johne R, Praefcke GJK et al (2021) Identification of the interferon-inducible GTPase GBP1 as major restriction factor for the hepatitis E virus. J Virol. https://doi.org/10.1128/jvi.01564-20 (Epub 2021/01/22)
Itsui Y, Sakamoto N, Kakinuma S, Nakagawa M, Sekine-Osajima Y, Tasaka-Fujita M et al (2009) Antiviral effects of the interferon-induced protein guanylate binding protein 1 and its interaction with the hepatitis C virus NS5B protein. Hepatology 50(6):1727–1737. https://doi.org/10.1002/hep.23195
Zhu Z, Shi Z, Yan W, Wei J, Shao D, Deng X et al (2013) Nonstructural protein 1 of influenza A virus interacts with human guanylate-binding protein 1 to antagonize antiviral activity. PLoS One 8(2):e55920. https://doi.org/10.1371/journal.pone.0055920 (Epub 2013/02/14)
Anderson SL, Carton JM, Lou J, Xing L, Rubin BY (1999) Interferon-induced guanylate binding protein-1 (GBP-1) mediates an antiviral effect against vesicular stomatitis virus and encephalomyocarditis virus. Virology 256(1):8–14. https://doi.org/10.1006/viro.1999.9614 (Epub 1999/03/24)
Pan W, Zuo X, Feng T, Shi X, Dai J (2012) Guanylate-binding protein 1 participates in cellular antiviral response to dengue virus. Virol J 9:292. https://doi.org/10.1186/1743-422x-9-292 (Epub 2012/11/29)
Nordmann A, Wixler L, Boergeling Y, Wixler V, Ludwig S (2012) A new splice variant of the human guanylate-binding protein 3 mediates anti-influenza activity through inhibition of viral transcription and replication. FASEB J 26(3):1290–1300. https://doi.org/10.1096/fj.11-189886
Krapp C, Hotter D, Gawanbacht A, McLaren Paul J, Kluge Silvia F, Stürzel Christina M et al (2016) Guanylate binding protein (GBP) 5 is an interferon-inducible inhibitor of HIV-1 infectivity. Cell Host Microbe 19(4):504–514. https://doi.org/10.1016/j.chom.2016.02.019
Srinivasachar Badarinarayan S, Shcherbakova I, Langer S, Koepke L, Preising A, Hotter D et al (2020) HIV-1 infection activates endogenous retroviral promoters regulating antiviral gene expression. Nucleic Acids Res 48(19):10890–10908. https://doi.org/10.1093/nar/gkaa832
Li Z, Qu X, Liu X, Huan C, Wang H, Zhao Z et al (2020) GBP5 is an interferon-induced inhibitor of respiratory syncytial virus. J Virol 94(21):e01407-e1420. https://doi.org/10.1128/JVI.01407-20
Feng J, Cao Z, Wang L, Wan Y, Peng N, Wang Q et al (2017) Inducible GBP5 mediates the antiviral response via interferon-related pathways during influenza A virus infection. J Innate Immun 9(4):419–435
Ma G, Huang J, Sun N, Liu X, Zhu M, Wu Z et al (2008) Molecular characterization of the porcine GBP1 and GBP2 genes. Mol Immunol 45(10):2797–2807. https://doi.org/10.1016/j.molimm.2008.02.007
Li LF, Yu J, Li Y, Wang J, Li S, Zhang L et al (2016) Guanylate-binding protein 1, an interferon-induced GTPase, exerts an antiviral activity against classical swine fever virus depending on its GTPase activity. J Virol 90(9):4412–4426. https://doi.org/10.1128/JVI.02718-15 (Epub 20160414)
Kommadath A, Bao H, Choi I, Reecy JM, Koltes JE, Fritz-Waters E et al (2017) Genetic architecture of gene expression underlying variation in host response to porcine reproductive and respiratory syndrome virus infection. Sci Rep 7:46203. https://doi.org/10.1038/srep46203 (Epub 20170410)
Khatun A, Nazki S, Jeong CG, Gu S, Mattoo SUS, Lee SI et al (2020) Effect of polymorphisms in porcine guanylate-binding proteins on host resistance to PRRSV infection in experimentally challenged pigs. Vet Res 51(1):14. https://doi.org/10.1186/s13567-020-00745-5 (Epub 20200219)
Koltes JE, Fritz-Waters E, Eisley CJ, Choi I, Bao H, Kommadath A et al (2015) Identification of a putative quantitative trait nucleotide in guanylate binding protein 5 for host response to PRRS virus infection. BMC Genom 16:412. https://doi.org/10.1186/s12864-015-1635-9 (Epub 20150528)
Gol S, Estany J, Fraile LJ, Pena RN (2015) Expression profiling of the GBP1 gene as a candidate gene for porcine reproductive and respiratory syndrome resistance. Anim Genet 46(6):599–606. https://doi.org/10.1111/age.12347 (Epub 20150911)
Gu T, Yu D, Fan Y, Wu Y, Yao YL, Xu L et al (2019) Molecular identification and antiviral function of the guanylate-binding protein (GBP) genes in the Chinese tree shrew (Tupaia belangeri chinesis). Dev Comp Immunol 96:27–36. https://doi.org/10.1016/j.dci.2019.02.014 (Epub 2019/03/01)
Wehner M, Herrmann C (2010) Biochemical properties of the human guanylate binding protein 5 and a tumor-specific truncated splice variant. FEBS J 277(7):1597–1605. https://doi.org/10.1111/j.1742-4658.2010.07586.x (Epub 2010/02/26)
Nantais DE, Schwemmle M, Stickney JT, Vestal DJ, Buss JE (1996) Prenylation of an interferon-gamma-induced GTP-binding protein: the human guanylate binding protein, huGBP1. J Leukoc Biol 60(3):423–431. https://doi.org/10.1002/jlb.60.3.423 (Epub 1996/09/01)
Modiano N, Lu YE, Cresswell P (2005) Golgi targeting of human guanylate-binding protein-1 requires nucleotide binding, isoprenylation, and an IFN-gamma-inducible cofactor. Proc Natl Acad Sci USA 102(24):8680–8685. https://doi.org/10.1073/pnas.0503227102 (Epub 2005/06/03)
Ngo CC, Man SM (2017) Mechanisms and functions of guanylate-binding proteins and related interferon-inducible GTPases: roles in intracellular lysis of pathogens. Cell Microbiol 19(12):e12791. https://doi.org/10.1111/cmi.12791
Santos JC, Broz P (2018) Sensing of invading pathogens by GBPs: at the crossroads between cell-autonomous and innate immunity. J Leukoc Biol 104(4):729–735. https://doi.org/10.1002/jlb.4mr0118-038r (Epub 2018/07/19)
Mostafavi S, Yoshida H, Moodley D, LeBoité H, Rothamel K, Raj T et al (2016) Parsing the interferon transcriptional network and its disease associations. Cell 164(3):564–578. https://doi.org/10.1016/j.cell.2015.12.032 (Epub 2016/01/30)
Degrandi D, Konermann C, Beuter-Gunia C, Kresse A, Würthner J, Kurig S et al (2007) Extensive characterization of IFN-induced GTPases mGBP1 to mGBP10 involved in host defense. J Immunol 179(11):7729–7740. https://doi.org/10.4049/jimmunol.179.11.7729
Kim BH, Shenoy AR, Kumar P, Das R, Tiwari S, MacMicking JD (2011) A family of IFN-γ-inducible 65-kD GTPases protects against bacterial infection. Science 332(6030):717–721. https://doi.org/10.1126/science.1201711
Gu T, Yu D, Xu L, Yao YL, Zheng X, Yao YG (2021) Tupaia guanylate-binding protein 1 interacts with vesicular stomatitis virus phosphoprotein and represses primary transcription of the viral genome. Cytokine 138:155388. https://doi.org/10.1016/j.cyto.2020.155388 (Epub 2020/12/04)
Gu T, Yu D, Xu L, Yao Y-L, Yao Y-G (2021) Tupaia GBP1 interacts with STING to initiate autophagy and restrict herpes simplex virus type 1 infection. J Immunol 207(11):2673. https://doi.org/10.4049/jimmunol.2100325
Li R, Zanin M, Xia X, Yang Z (2018) The tree shrew as a model for infectious diseases research. J Thorac Dis 10(Suppl 19):S2272–S2279. https://doi.org/10.21037/jtd.2017.12.121 (Epub 2018/08/18)
Xu L, Yu DD, Ma YH, Yao YL, Luo RH, Feng XL et al (2020) COVID-19-like symptoms observed in Chinese tree shrews infected with SARS-CoV-2. Zool Res 41(5):517–526. https://doi.org/10.24272/j.issn.2095-8137.2020.053 (Epub 2020/07/24)
Carter CC, Gorbacheva VY, Vestal DJ (2005) Inhibition of VSV and EMCV replication by the interferon-induced GTPase, mGBP-2: differential requirement for wild-type GTP binding domain. Arch Virol 150(6):1213–1220. https://doi.org/10.1007/s00705-004-0489-2 (Epub 2005/02/18)
Yu P, Li Y, Li Y, Miao Z, Peppelenbosch MP, Pan Q (2020) Guanylate-binding protein 2 orchestrates innate immune responses against murine norovirus and is antagonized by the viral protein NS7. J Biol Chem 295(23):8036–8047. https://doi.org/10.1074/jbc.RA120.013544 (Epub 2020/04/30)
Degrandi D, Kravets E, Konermann C, Beuter-Gunia C, Klümpers V, Lahme S et al (2013) Murine guanylate binding protein 2 (mGBP2) controls Toxoplasma gondii replication. Proc Natl Acad Sci USA 110(1):294–299. https://doi.org/10.1073/pnas.1205635110 (Epub 2012/12/19)
Cerqueira DM, Gomes MTR, Silva ALN, Rungue M, Assis NRG, Guimarães ES et al (2018) Guanylate-binding protein 5 licenses caspase-11 for Gasdermin-D mediated host resistance to Brucella abortus infection. PLoS Pathog 14(12):e1007519-e. https://doi.org/10.1371/journal.ppat.1007519
Corsetti PP, de Almeida LA, Gonçalves ANA, Gomes MTR, Guimarães ES, Marques JT et al (2018) miR-181a-5p regulates TNF-α and miR-21a-5p influences gualynate-binding protein 5 and IL-10 expression in macrophages affecting host control of Brucella abortus infection. Front Immunol 9:1331. https://doi.org/10.3389/fimmu.2018.01331 (Epub 2018/06/27)
Man SM, Karki R, Malireddi RK, Neale G, Vogel P, Yamamoto M et al (2015) The transcription factor IRF1 and guanylate-binding proteins target activation of the AIM2 inflammasome by Francisella infection. Nat Immunol 16(5):467–475. https://doi.org/10.1038/ni.3118 (Epub 2015/03/17)
Place DE, Malireddi RKS, Kim J, Vogel P, Yamamoto M, Kanneganti T-D (2021) Osteoclast fusion and bone loss are restricted by interferon inducible guanylate binding proteins. Nat Commun 12(1):496. https://doi.org/10.1038/s41467-020-20807-8
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H et al (2000) The protein data bank. Nucleic Acids Res 28(1):235–242. https://doi.org/10.1093/nar/28.1.235 (Epub 1999/12/11)
Sehnal D, Bittrich S, Deshpande M, Svobodová R, Berka K, Bazgier V et al (2021) Mol* Viewer: modern web app for 3D visualization and analysis of large biomolecular structures. Nucleic Acids Res 49(W1):W431–W437. https://doi.org/10.1093/nar/gkab314
Acknowledgements
This work was supported by Fundação para a Ciência e Tecnologia (FCT) through the PhD fellowship of J.V.C.R. (DFA/BD/4965/2020), the Assistant Researcher grant of J.A. (CEECIND/00078/2017) and the Principal Researcher grant of P.J.E. (CEECIND/01495/2020). H-M.B. acknowledges funding from the Deutsche Forschungsgemeinschaft (DFG) (BA-6820/1-1). H-M.B. and J.A. acknowledge the project-related personal exchange (PPP) program of the FCT/German Academic Exchange Service (DAAD) (57518622).
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Schelle, L., Côrte-Real, J.V., Esteves, P.J. et al. Functional cross-species conservation of guanylate-binding proteins in innate immunity. Med Microbiol Immunol 212, 141–152 (2023). https://doi.org/10.1007/s00430-022-00736-7
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DOI: https://doi.org/10.1007/s00430-022-00736-7