A Role for the Human Nucleotide-binding Domain, Leucine-rich Repeat-containing Family Member NLRC5 in Antiviral Responses

Proteins of the nucleotide-binding domain, leucine-rich repeat (NLR)-containing family recently gained attention as important components of the innate immune system. Although over 20 of these proteins are present in humans, only a few members including the cytosolic pattern recognition receptors NOD1, NOD2, and NLRP3 have been analyzed extensively. These NLRs were shown to be pivotal for mounting innate immune response toward microbial invasion. Here we report on the characterization of human NLRC5 and provide evidence that this NLR has a function in innate immune responses. We found that NLRC5 is a cytosolic protein expressed predominantly in hematopoetic cells. NLRC5 mRNA and protein expression was inducible by the double-stranded RNA analog poly(I·C) and Sendai virus. Overexpression of NLRC5 failed to trigger inflammatory responses such as the NF-κB or interferon pathways in HEK293T cells. However, knockdown of endogenous NLRC5 reduced Sendai virus- and poly(I·C)-mediated type I interferon pathway-dependent responses in THP-1 cells and human primary dermal fibroblasts. Taken together, this defines a function for NLRC5 in anti-viral innate immune responses. Proteins of the nucleotide-binding domain, leucine-rich repeat (NLR)-containing family recently gained attention as important components of the innate immune system. Although over 20 of these proteins are present in humans, only a few members including the cytosolic pattern recognition receptors NOD1, NOD2, and NLRP3 have been analyzed extensively. These NLRs were shown to be pivotal for mounting innate immune response toward microbial invasion. Here we report on the characterization of human NLRC5 and provide evidence that this NLR has a function in innate immune responses. We found that NLRC5 is a cytosolic protein expressed predominantly in hematopoetic cells. NLRC5 mRNA and protein expression was inducible by the double-stranded RNA analog poly(I·C) and Sendai virus. Overexpression of NLRC5 failed to trigger inflammatory responses such as the NF-κB or interferon pathways in HEK293T cells. However, knockdown of endogenous NLRC5 reduced Sendai virus- and poly(I·C)-mediated type I interferon pathway-dependent responses in THP-1 cells and human primary dermal fibroblasts. Taken together, this defines a function for NLRC5 in anti-viral innate immune responses. IntroductionInnate immunity and induction of adaptive immune responses are based on the recognition of conserved signatures of microbes and “danger signals” released from infected host cells. These pathogen-associated molecular patterns (PAMPs) 2The abbreviations used are: PAMPpathogen-associated molecular patternDAMPdanger-associated molecular patternLRRleucine-rich repeatsCARDcaspase activation and recruitment domainPYDpyrin domainDDdeath domainSeVSendai virusNLRnucleotide-binding domain, leucine-rich repeat-containingMAPKmitogen-activated protein kinaseRTreverse transcriptionGAPDHglyceraldehyde-3-phosphate dehydrogenaseIFNinterferonsiRNAsmall interfering RNAGFPgreen fluorescent proteinHRPhorseradish peroxidaseELISAenzyme-linked immunosorbent assayRANTESregulated upon activation, normal T cell expressed, and secreted. and danger-associated molecular patterns (DAMPs) are recognized by so-called pattern recognition receptors in the host and trigger inflammatory responses (1Akira S. Uematsu S. Takeuchi O. Cell. 2006; 124: 783-801Abstract Full Text Full Text PDF PubMed Scopus (8551) Google Scholar). Different types of pattern recognition receptors show distinct subcellular localization, allowing the host to react to extracellular, vesicular, and cytosolic presented PAMPs and DAMPs. One class of pattern recognition receptors, the nucleotide-binding domain, leucine-rich repeat (NLR)-containing protein family, gained much attention because it was shown that members of this family are critically involved in mounting immune responses to bacterial peptidoglycan fragments and in controlling release of the key inflammatory cytokine interleukin-1β (2Fritz J.H. Ferrero R.L. Philpott D.J. Girardin S.E. Nat. Immunol. 2006; 7: 1250-1257Crossref PubMed Scopus (701) Google Scholar, 3Kufer T.A. Mol. Biosyst. 2008; 4: 380-386Crossref PubMed Scopus (41) Google Scholar, 4Martinon F. Mayor A. Tschopp J. Annu. Rev. Immunol. 2009; 27: 229-265Crossref PubMed Scopus (1837) Google Scholar). Over 20 NLRs are encoded in the human genome. As a hallmark they share a tripartite molecular architecture with a centrally located ATPase domain, a NACHT domain (domain present in NAIP, CIITA, HET-E, TP-1) that mediates oligomerization and activation of these proteins, followed by a leucine-rich repeat region (LRR) at the C terminus. With the only exceptions of NLRX1 and NAIP, the N-terminal part of the NLRs consists of a domain that adopts a death domain fold. Most NLR members thereby have either a caspase activation and recruitment domain (CARD) or a pyrin domain (PYD), connecting the respective NLR to different downstream signaling events (2Fritz J.H. Ferrero R.L. Philpott D.J. Girardin S.E. Nat. Immunol. 2006; 7: 1250-1257Crossref PubMed Scopus (701) Google Scholar). Well studied examples of CARD domain-containing NLRs are NOD1 and NOD2, which react to peptidoglycan fragments and lead to NF-κB, MAPK, and caspase activation (3Kufer T.A. Mol. Biosyst. 2008; 4: 380-386Crossref PubMed Scopus (41) Google Scholar). Examples of PYD containing NLRs comprise NLRP1 and NLRP3, which form high molecular weight platforms, so-called inflammasomes that lead to activation of caspase-1 and subsequent interleukin-1β release upon encounter of DAMPs and certain PAMPs (4Martinon F. Mayor A. Tschopp J. Annu. Rev. Immunol. 2009; 27: 229-265Crossref PubMed Scopus (1837) Google Scholar).NLRC5 (alternatively named NOD27 or CLR16.1) is an interesting exception in the NLR family. It has a typical NLR architecture but contains an effector domain, predicted to adopt a death domain (DD) fold without obvious homology to the CARD and PYD domains found in other NLRs. Furthermore, it possesses the longest LRR domain of all human NLR members. Alignment of the LRR domains shows that within the NLR family NLRC5 is most closely related to NOD1, NOD2, and NLRC3 (5Istomin A.Y. Godzik A. BMC Immunol. 2009; 10: 48Crossref PubMed Scopus (31) Google Scholar). This is further confirmed by sequence comparison of the NACHT domains, which puts NLRC5 in evolutionary vicinity to NOD1, NOD2, and NLRC3 (6Hughes A.L. Immunogenetics. 2006; 58: 785-791Crossref PubMed Scopus (27) Google Scholar, 7Proell M. Riedl S.J. Fritz J.H. Rojas A.M. Schwarzenbacher R. PLoS One. 2008; 3e2119Crossref PubMed Scopus (263) Google Scholar). NOD1 and NOD2 are well characterized NLRs with a critical function in controlling immune responses toward bacterial challenge and likely also viral challenge (2Fritz J.H. Ferrero R.L. Philpott D.J. Girardin S.E. Nat. Immunol. 2006; 7: 1250-1257Crossref PubMed Scopus (701) Google Scholar, 8Sabbah A. Chang T.H. Harnack R. Frohlich V. Tominaga K. Dube P.H. Xiang Y. Bose S. Nat. Immunol. 2009; 10: 1073-1080Crossref PubMed Scopus (530) Google Scholar). Moreover, NLRC3 was proposed to function as a negative regulator in T cells (9Conti B.J. Davis B.K. Zhang J. O'connor Jr., W. Williams K.L. Ting J.P. J. Biol. Chem. 2005; 280: 18375-18385Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). This suggested that NLRC5 might also be involved in innate immune responses in humans. Interestingly, all of the mentioned NLRs are localized on the same chromosomal region. However, the biological relevance of this fact remains elusive (10Ting J.P. Davis B.K. Annu. Rev. Immunol. 2005; 23: 387-414Crossref PubMed Scopus (298) Google Scholar). In the present study we characterize human NLRC5, revealing a function in anti-viral innate immune responses in human cells.DISCUSSIONHere we report on the characterization of human NLRC5. Alignment of its LRR and NACHT domains shows that NLRC5 is related to the NLRs NOD1, NOD2, and NLRC3 (5Istomin A.Y. Godzik A. BMC Immunol. 2009; 10: 48Crossref PubMed Scopus (31) Google Scholar, 6Hughes A.L. Immunogenetics. 2006; 58: 785-791Crossref PubMed Scopus (27) Google Scholar, 7Proell M. Riedl S.J. Fritz J.H. Rojas A.M. Schwarzenbacher R. PLoS One. 2008; 3e2119Crossref PubMed Scopus (263) Google Scholar), which are involved in the regulation of innate immune responses. NLRC5 is an interesting exception in the NLR family because it (i) contains an effector domain that adopts a DD fold but lacks recognizable homology to the CARD and PYD domains found in other NLRs and (ii) has an unusually long LRR domain. Modeling of this LRR domain of NLRC5 suggested that it forms a large helical conformation (Fig. 1A). However, because this interpretation is purely based on modeling, it is also possible that it adopts a torroid-like structure or connected circles as recently proposed by others (5Istomin A.Y. Godzik A. BMC Immunol. 2009; 10: 48Crossref PubMed Scopus (31) Google Scholar). The LRR domains of the human NLR proteins are essential for sensing of their cognate PAMPs and DAMPs (2Fritz J.H. Ferrero R.L. Philpott D.J. Girardin S.E. Nat. Immunol. 2006; 7: 1250-1257Crossref PubMed Scopus (701) Google Scholar). Furthermore, evidence for changes of the LRR composition of innate immune receptors exists. One intriguing example is given by the ancient VLR proteins in agnathes, which can generate diverse sensing variety by changing the composition of their LRR domains (27Pancer Z. Amemiya C.T. Ehrhardt G.R. Ceitlin J. Gartland G.L. Cooper M.D. Nature. 2004; 430: 174-180Crossref PubMed Scopus (526) Google Scholar). The unusual structure of the NLRC5 LRR domain might thus be indicative for NLRC5 to respond to quite different stimuli than other NLRs. Accordingly, the isoforms of NLRC5 described here that encoded for changed LRR structures might give rise to changed elicitor sensing spectra of the corresponding proteins. Although the detailed biological function of these NLRC5 isoforms awaits establishment in vivo, we found tissue-specific expression of at least two splice variants of NLRC5 lacking the LRRs or parts thereof. High expression of a variant lacking the whole LRR region (isoform 3) in T cells might be indicative of a regulatory role of the encoded protein in these cells. Future studies shall address in detail the function of this isoform.NLRC5 mRNA was found to be expressed in hematopoietic cells including monocytes, T cells, and B cells. Of note, this basal expression pattern in primary tissue mimics that of NLRC3, a NLR suggested to be involved in negative regulation of T cells (9Conti B.J. Davis B.K. Zhang J. O'connor Jr., W. Williams K.L. Ting J.P. J. Biol. Chem. 2005; 280: 18375-18385Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar), making it tempting to speculate that these two NLRs might be functionally linked. NLRC5 mRNA and protein levels were induced by the TLR3 ligand poly(I·C) and Sendai virus infection in nonhematopoietic cells such as HeLa. Thus, NLRC5 is up-regulated by both single-stranded and double-stranded RNA viruses and/or viral signatures. Notably, in THP-1 cells we only observed a marginal induction of NLRC5 levels after poly(I·C) and Sendai virus challenge, respectively (Fig. 3). In line with the observed high basal NLRC5 expression in THP-1 cells and its low expression in HeLa cells, this suggests that NLRC5 expression is differentially regulated in various cell types; although myeloid cells have already high basal expression levels of NLRC5, assuring sufficient response to the cognate stimulus, nonhematopoietic cells might be required to gain NLRC5 competence by induction of NLRC5 expression upon exposure to inflammatory milieu. Such a positive feedback loop is known for other NLRs. Although our data, in particular direct targeting of the TLR3 pathway, suggested that NLRC5 expression is under direct control of the type I interferon pathway, we cannot exclude that the induction is due to release of secondary effectors upon interferon activation by an autocrine loop.To elucidate the molecular connection of NLRC5 to innate immune pathways, we further aimed to identify interaction partners and signaling pathways linked to the NLRC5 effector domain. Kuenzel et al. (28Kuenzel S. Till A. Winkler M. Häsler R. Lipinski S. Jung S. Grötzinger J. Fickenscher H. Schreiber S. Rosenstiel P. J. Immunol. 2010; 184: 1990-2000Crossref PubMed Scopus (147) Google Scholar) recently reported activation of a ISRE and GAS reporter induced by overexpression of a GFP-tagged version of NLRC5 and forced dimerization of the NLRC5 death domain in HeLaS3 cells. We, however, could not observe activation of an ISRE reporter also with an N-terminal GFP-tagged version of NLRC5 in HEK293T (data not shown), suggesting that HEK293T cells might lack an essential adaptor for NLRC5 signaling. In line, overexpression of NLRC5 did not yield activation of other canonical inflammatory pathways in HEK293T cells (Fig. 4), including p38 MAPK (data not shown). We thereby can exclude that a putative negative regulation by the LRR domain as a form of NLRC5 lacking the LRR domain (isoform 3) led to the same results. In contrast, overexpression of NLRC5 significantly impaired type I interferon reporter activation in HEK293T cells without affecting NF-κB responses, supporting a role for NLRC5 in type I interferon responses (supplemental Fig. S3). This effect was likely due to titration of a factor involved in the type I interferon pathway. Co-immunoprecipitation experiments using educated guesses, including TBK1, SINTBAD, TANK1, NAP1, IKK∈, and IRF3, 7, and 5, as well as unbiased yeast two-hybrid screening of NLRC5 and its DD, were conducted to address this observation in more detail (data not shown). Unfortunately, the results did not allow us to link NLRC5 to any known component of the type I interferon pathway yet. Of note, recent studies also failed to reveal robust interactions between NLRC5 and known NLR adaptor proteins such as RIP2K and ASC (29Dowds T.A. Masumoto J. Chen F.F. Ogura Y. Inohara N. Núñez G. Biochem. Biophys. Res. Commun. 2003; 302: 575-580Crossref PubMed Scopus (133) Google Scholar, 30Wagner R.N. Proell M. Kufer T.A. Schwarzenbacher R. PLoS One. 2009; 4e4931Crossref PubMed Scopus (47) Google Scholar).However, clear physiological evidence for a role of NLRC5 in anti-viral responses could be obtained by controlled siRNA studies in the myeloid-like THP-1 cell line. Knockdown of endogenous NLRC5 in these cells robustly impaired the type I interferon response as shown by reduced IFN-β release and lower IFN-β and IP-10 mRNA induction upon SeV infection (Fig. 5 and supplemental Fig. S1). We expanded these findings by analyzing other SeV-induced cytokines (supplemental Fig. S1). This revealed that among others the induction and release of the important early phase chemokine RANTES (CCL5) was also negatively affected upon NLRC5 knockdown (Fig. 5). RANTES is known to be released upon SeV infection also from primary human cells (25Hua J. Liao M.J. Rashidbaigi A. J. Leukocyte Biol. 1996; 60: 125-128Crossref PubMed Scopus (28) Google Scholar, 26Matikainen S. Pirhonen J. Miettinen M. Lehtonen A. Govenius-Vintola C. Sareneva T. Julkunen I. Virology. 2000; 276: 138-147Crossref PubMed Scopus (111) Google Scholar). Indeed, we could substantiate the observation made in THP-1 cells in primary human dermal fibroblast from different donors (Fig. 6) where knockdown of NLRC5 by two different siRNA duplexes led again to a robust reduction of both SeV- and poly(I·C)-induced type I interferon and RANTES release in these cells. Importantly, IP-10, IFN-β, and RANTES induction is directly dependent on activation of IRF3 by the interferon pathway (31Andersen J. VanScoy S. Cheng T.F. Gomez D. Reich N.C. Genes Immun. 2008; 9: 168-175Crossref PubMed Scopus (78) Google Scholar, 32Lin R. Heylbroeck C. Genin P. Pitha P.M. Hiscott J. Mol. Cell. Biol. 1999; 19: 959-966Crossref PubMed Scopus (250) Google Scholar), suggesting that NLRC5 has an impact on this pathway. In conclusion, our data show that NLRC5 is involved in regulating the type I interferon pathway.Taken together, our data support a role for NLRC5 in viral innate immune responses and put it on the list of NLR proteins with proposed functions in viral recognition such as NLRP3 (33Delaloye J. Roger T. Steiner-Tardivel Q.G. Le Roy D. Knaup Reymond M. Akira S. Petrilli V. Gomez C.E. Perdiguero B. Tschopp J. Pantaleo G. Esteban M. Calandra T. PLoS Pathog. 2009; 5e1000480Crossref PubMed Scopus (259) Google Scholar, M. A. J.H. J. D. Inohara N. Núñez G. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, V. Tschopp J. Nature. 2008; PubMed Scopus Google Scholar), NOD2 A. Chang T.H. Harnack R. Frohlich V. Tominaga K. Dube P.H. Xiang Y. Bose S. Nat. Immunol. 2009; 10: 1073-1080Crossref PubMed Scopus (530) Google Scholar, I. A. T. S.J. A. N. Cell. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar), and NLRX1 Y. Z. Chen Z. Ting J.P. Nature. 2008; PubMed Scopus Google Scholar). Of note, all of these NLRs respond to RNA to the cognate for NLRC5 by known However, single-stranded as well as and failed to robust interferon or NF-κB responses in HEK293T cells (data not the molecular function of NLRC5 remains we can only speculate on its of One tempting is that NLRC5 might in with other NLRs. for the of such NLR V. K. Biochem. J. 2004; PubMed Scopus Google Scholar). Furthermore, NOD2 and have been recently as involved in mounting interferon responses toward virus infection I. A. T. S.J. A. N. Cell. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar), and NOD2 might be to directly single-stranded RNA A. Chang T.H. Harnack R. Frohlich V. Tominaga K. Dube P.H. Xiang Y. Bose S. Nat. Immunol. 2009; 10: 1073-1080Crossref PubMed Scopus (530) Google Scholar). It is that we observed a interaction of NLRC5 with both NOD2 and in a using proteins. K. M. R. and T. A. results. Although the biological relevance of these findings remains elusive for endogenous proteins, could a where NLRC5 might not only responses to viral but at the same might impact on studies are to the function of this interesting NLR protein in innate immune responses to viral and its with other NLR members in more on our however, we that a lack of NLRC5 or negatively the of the host upon viral the of this NLRC5 was found to have a role also in immune responses (28Kuenzel S. Till A. Winkler M. Häsler R. Lipinski S. Jung S. Grötzinger J. Fickenscher H. Schreiber S. Rosenstiel P. J. Immunol. 2010; 184: 1990-2000Crossref PubMed Scopus (147) Google Scholar). This further our findings and suggests that NLRC5 might be involved in anti-viral responses more in because contains a double-stranded genome. IntroductionInnate immunity and induction of adaptive immune responses are based on the recognition of conserved signatures of microbes and “danger signals” released from infected host cells. These pathogen-associated molecular patterns (PAMPs) 2The abbreviations used are: PAMPpathogen-associated molecular patternDAMPdanger-associated molecular patternLRRleucine-rich repeatsCARDcaspase activation and recruitment domainPYDpyrin domainDDdeath domainSeVSendai virusNLRnucleotide-binding domain, leucine-rich repeat-containingMAPKmitogen-activated protein kinaseRTreverse transcriptionGAPDHglyceraldehyde-3-phosphate dehydrogenaseIFNinterferonsiRNAsmall interfering RNAGFPgreen fluorescent proteinHRPhorseradish peroxidaseELISAenzyme-linked immunosorbent assayRANTESregulated upon activation, normal T cell expressed, and secreted. and danger-associated molecular patterns (DAMPs) are recognized by so-called pattern recognition receptors in the host and trigger inflammatory responses (1Akira S. Uematsu S. Takeuchi O. Cell. 2006; 124: 783-801Abstract Full Text Full Text PDF PubMed Scopus (8551) Google Scholar). Different types of pattern recognition receptors show distinct subcellular localization, allowing the host to react to extracellular, vesicular, and cytosolic presented PAMPs and DAMPs. One class of pattern recognition receptors, the nucleotide-binding domain, leucine-rich repeat (NLR)-containing protein family, gained much attention because it was shown that members of this family are critically involved in mounting immune responses to bacterial peptidoglycan fragments and in controlling release of the key inflammatory cytokine interleukin-1β (2Fritz J.H. Ferrero R.L. Philpott D.J. Girardin S.E. Nat. Immunol. 2006; 7: 1250-1257Crossref PubMed Scopus (701) Google Scholar, 3Kufer T.A. Mol. Biosyst. 2008; 4: 380-386Crossref PubMed Scopus (41) Google Scholar, 4Martinon F. Mayor A. Tschopp J. Annu. Rev. Immunol. 2009; 27: 229-265Crossref PubMed Scopus (1837) Google Scholar). Over 20 NLRs are encoded in the human genome. As a hallmark they share a tripartite molecular architecture with a centrally located ATPase domain, a NACHT domain (domain present in NAIP, CIITA, HET-E, TP-1) that mediates oligomerization and activation of these proteins, followed by a leucine-rich repeat region (LRR) at the C terminus. With the only exceptions of NLRX1 and NAIP, the N-terminal part of the NLRs consists of a domain that adopts a death domain fold. Most NLR members thereby have either a caspase activation and recruitment domain (CARD) or a pyrin domain (PYD), connecting the respective NLR to different downstream signaling events (2Fritz J.H. Ferrero R.L. Philpott D.J. Girardin S.E. Nat. Immunol. 2006; 7: 1250-1257Crossref PubMed Scopus (701) Google Scholar). Well studied examples of CARD domain-containing NLRs are NOD1 and NOD2, which react to peptidoglycan fragments and lead to NF-κB, MAPK, and caspase activation (3Kufer T.A. Mol. Biosyst. 2008; 4: 380-386Crossref PubMed Scopus (41) Google Scholar). Examples of PYD containing NLRs comprise NLRP1 and NLRP3, which form high molecular weight platforms, so-called inflammasomes that lead to activation of caspase-1 and subsequent interleukin-1β release upon encounter of DAMPs and certain PAMPs (4Martinon F. Mayor A. Tschopp J. Annu. Rev. Immunol. 2009; 27: 229-265Crossref PubMed Scopus (1837) Google Scholar).NLRC5 (alternatively named NOD27 or CLR16.1) is an interesting exception in the NLR family. It has a typical NLR architecture but contains an effector domain, predicted to adopt a death domain (DD) fold without obvious homology to the CARD and PYD domains found in other NLRs. Furthermore, it possesses the longest LRR domain of all human NLR members. Alignment of the LRR domains shows that within the NLR family NLRC5 is most closely related to NOD1, NOD2, and NLRC3 (5Istomin A.Y. Godzik A. BMC Immunol. 2009; 10: 48Crossref PubMed Scopus (31) Google Scholar). This is further confirmed by sequence comparison of the NACHT domains, which puts NLRC5 in evolutionary vicinity to NOD1, NOD2, and NLRC3 (6Hughes A.L. Immunogenetics. 2006; 58: 785-791Crossref PubMed Scopus (27) Google Scholar, 7Proell M. Riedl S.J. Fritz J.H. Rojas A.M. Schwarzenbacher R. PLoS One. 2008; 3e2119Crossref PubMed Scopus (263) Google Scholar). NOD1 and NOD2 are well characterized NLRs with a critical function in controlling immune responses toward bacterial challenge and likely also viral challenge (2Fritz J.H. Ferrero R.L. Philpott D.J. Girardin S.E. Nat. Immunol. 2006; 7: 1250-1257Crossref PubMed Scopus (701) Google Scholar, 8Sabbah A. Chang T.H. Harnack R. Frohlich V. Tominaga K. Dube P.H. Xiang Y. Bose S. Nat. Immunol. 2009; 10: 1073-1080Crossref PubMed Scopus (530) Google Scholar). Moreover, NLRC3 was proposed to function as a negative regulator in T cells (9Conti B.J. Davis B.K. Zhang J. O'connor Jr., W. Williams K.L. Ting J.P. J. Biol. Chem. 2005; 280: 18375-18385Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). This suggested that NLRC5 might also be involved in innate immune responses in humans. Interestingly, all of the mentioned NLRs are localized on the same chromosomal region. However, the biological relevance of this fact remains elusive (10Ting J.P. Davis B.K. Annu. Rev. Immunol. 2005; 23: 387-414Crossref PubMed Scopus (298) Google Scholar). In the present study we characterize human NLRC5, revealing a function in anti-viral innate immune responses in human cells.

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