Abstract
Antiviral immunity against a pathogen is mounted upon recognition by the host of virally associated structures. One of these viral ‘signatures’, double-stranded (ds) RNA, is a replication product of most viruses within infected cells and is sensed by Toll-like receptor 3 (TLR3) and the recently identified cytosolic RNA helicases RIG-I (retinoic acid inducible gene I, also known as Ddx58) and Mda5 (melanoma differentiation-associated gene 5, also known as Ifih1 or Helicard)1. Both helicases detect dsRNA, and through their protein-interacting CARD domains, relay an undefined signal resulting in the activation of the transcription factors interferon regulatory factor 3 (IRF3) and NF-κB. Here we describe Cardif, a new CARD-containing adaptor protein that interacts with RIG-I and recruits IKKα, IKKβ and IKKɛ kinases by means of its C-terminal region, leading to the activation of NF-κB and IRF3. Overexpression of Cardif results in interferon-β and NF-κB promoter activation, and knockdown of Cardif by short interfering RNA inhibits RIG-I-dependent antiviral responses. Cardif is targeted and inactivated by NS3-4A, a serine protease from hepatitis C virus known to block interferon-β production. Cardif thus functions as an adaptor, linking the cytoplasmic dsRNA receptor RIG-I to the initiation of antiviral programmes.
Similar content being viewed by others
Main
Innate immune responses defend the host from invading pathogens by recognizing pathogen-associated molecular patterns. Toll-like receptors are transmembrane receptors that use their leucine-rich repeats to recognize pathogen-associated molecular patterns and initiate intracellular responses through recruitment of TIR-domain containing adaptors (see ref. 2 for a review). TLR3 acts as an antiviral receptor that is capable of recognizing dsRNA. TLR3 transmits cellular responses by specifically recruiting the TIR-containing adaptor protein Trif (also known as TICAM1). Triggering of TLR3 results in a massive type-I interferon (IFN) response, as Trif is able to recruit the essential IRF-3-activating kinases TBK1 and IKKɛ3,4. However, the importance of TLR3 in the generation of antiviral immune responses has been recently challenged, as TLR3 is not required to mount antiviral responses against some viruses5, suggesting the existence of TLR3-independent dsRNA recognition systems.
Recently, two DexD/H box RNA helicases, RIG-I and Helicard (Mda5), were found to participate in the cytoplasmic recognition of dsRNA6,7. Expression of RIG-I and Helicard can be induced by retinoic acid and IFN-β treatment, respectively. Both helicases contain two amino-terminal caspase recruitment domains (CARD) and a C-terminal region that is characterized by the presence of a helicase domain8,9. RIG-I (and probably Helicard) is able to interact with cytoplasmic dsRNA7,10, and we have previously shown that Helicard is cleaved during apoptosis11. RIG-I and Helicard initiate antiviral responses by activating the transcription factors IRF3 and NF-κB, resulting in an enhanced transcription of type-I IFN6,7. The region responsible for RIG-I-induced downstream signalling was mapped to the N-terminal CARD domains, suggesting the existence of a putative CARD adaptor molecule7,10 that relays the signal.
In an attempt to identify new CARD-domain-containing proteins, we performed profile searches in human protein databases, which led us to the identification of a protein that we named CARD adaptor inducing IFN-β (Cardif). Cardif contains 540 amino acids and has a N-terminal CARD domain similar to the CARD domains of RIG-I and Helicard (Fig. 1a, b). Cardif corresponds to a gene previously identified in a complementary DNA library screen of potential NF-κB-activating molecules12. Polymerase chain reaction with reverse transcription (RT–PCR) of different human cell lines, primary cells and tissues revealed broad expression of Cardif (Supplementary Fig. 1).
Because Cardif is characterized by the presence of a N-terminal CARD domain that is similar to RIG-I and Helicard, we investigated whether the helicases could interact with Cardif upon overexpression of Cardif in human embryonic kidney (HEK) 293T cells. Cardif interacted with RIG-I and showed a weak interaction with Helicard, but did not interact with any of the other tested CARD-domain-containing proteins (Fig. 1c). Cardif oligomerization through its CARD domain was not detected under these experimental conditions.
In subsequent experiments we concentrated on the functional consequences of the RIG-I–Cardif interaction. Overexpression of full-length Cardif in 293T cells resulted in dose-dependent activation of NF-κB- and IFN-β-reporter plasmids, as well as the IFN-stimulated response element (ISRE) of ISG54, an IRF3-dependent promoter (Fig. 2a). Similar activation was also observed in HeLa cells (data not shown). Overexpression of a deletion construct containing only the CARD domain did not result in activation of any of the reporter genes tested. However, a construct lacking the N-terminal CARD domain (ΔCARD) was sufficient to drive activation of the reporter genes, but to a much lesser extent than the wild-type construct. Activation of the ISRE reporter gene was dependent on IRF3 (Supplementary Fig. 2), as a dominant-negative version of IRF3 lacking the N-terminal DNA-binding region (IRF3 ΔN) inhibited Cardif- and also Trif-induced activation of ISRE, but did not prevent NF-κB activation. A non-phosphorylable form of IκB (dominant-negative IκB) inhibited Cardif- and Trif-induced NF-κB activation only. Overexpression of Cardif was sufficient to induce transcription of interferon-β (Ifnb1) and of the NF-κB target gene interleukin 6 (Il6) in mouse embryonic fibroblasts (MEFs), as well as inducing the activation of endogenous IRF3 by phosphorylation13 and IRF3-dependent production of RANTES in 293T cells (Fig. 2b, c).
Together, these results suggest that the carboxy-terminal region of Cardif might be implicated in the recruitment and activation of IKK kinase complexes that are essential for the activation of NF-κB and IRF3. Indeed, we found that Cardif interacted with IKKɛ (which is able to phosphorylate IRF3) and with IKKα and IKKβ (which are known to phosphorylate IκB), but not with TBK1 (Fig. 3a). This recruitment was more evident for the Cardif mutant containing a deleted CARD domain than for the full-length protein. The Cardif–IKKɛ interaction contrasts with the propensity of Trif to preferentially interact with TBK1 as opposed to IKKɛ14. This suggests that Trif and Cardif use two different IKK kinases to phosphorylate IRF3, although this might be cell-type-specific.
To unambiguously demonstrate that Cardif acts downstream of RIG-I in antiviral signalling, we overexpressed RIG-I in 293T cells to induce activation of the IFN-β luciferase promoter, and monitored the consequence of using siRNA to knock down the expression of Cardif, RIG-I and Trif (Fig. 3b). Western blotting showed that all three siRNAs efficiently reduced the protein levels of their respective targets (Supplementary Fig. 3). As a consequence of Cardif knockdown, RIG-I-induced, but not Trif-induced IFN-β promoter activation was greatly reduced (Fig. 3b). Notably, although Trif siRNA inhibited Trif-induced IFN-β promoter activation, it increased the IFN-β response triggered by the overexpression of RIG-I, suggesting that RIG-I may act as a sensor of siRNA within the cytoplasm.
Next, we sought to determine whether Cardif siRNA can inhibit an IFN response in the context of stimulation with dsRNA or infection with Sendai virus (SenV), a virus that triggers RIG-I-dependent IFN responses10. As neither Poly(I:C) transfection nor SenV infection of 293T cells resulted in an activation of the IFN-β promoter per se, we reasoned that RIG-I, which is an inducible gene, might not be expressed under these conditions. We therefore transfected a small amount of RIG-I, which permitted us to observe a synergistic effect of SenV or Poly(I:C) on IFN activation (Fig. 3c, d). Cardif knockdown inhibited both Poly(I:C)- and SenV-induced IFN-β promoter activation. To confirm these findings, vesicular stomatitis virus (VSV) was used to infect primary MEFs that depend on RIG-I to mount an antiviral response15. Cardif knockdown by siRNA inhibited VSV-triggered RANTES expression (Fig. 3e). Together, these results demonstrate the important role of Cardif as an adaptor of RIG-I-dependent antiviral immune responses.
Several human pathogenic viruses, including influenza virus, vaccinia virus and Ebola virus, have evolved strategies to inhibit the early signalling events that lead to IFN production16. NS3-4A, a multifunctional protein of hepatitis C virus (HCV) that has serine protease activity essential for the production of mature viral proteins, has recently been shown to block the activation of IRF3 (ref. 17). NS3-4A counteracts TLR3-dependent pathways by targeting Trif for proteolytic cleavage, and also counteracts TLR3-independent pathways by targeting an undefined protein of the RIG-I-dependent pathway18,19. IKKɛ overexpresison was shown to overcome NS3-4A-mediated block of IRF3 activation, suggesting that this viral protease targets an adaptor protein ‘upstream’ of IKKɛ20.
We therefore hypothesized that Cardif might be a substrate for NS3-4A. Indeed, Cardif is cleaved by wild-type but not by a catalytically inactive form of NS3-4A (Fig. 4a). Trif was also cleaved by NS3-4A under the same conditions, as previously reported18. The N- and C-terminally tagged cleavage fragments of Cardif allowed us to map the cleavage site to within 5 kDa of the C terminus (Fig. 4a). As NS3-4A is known to specifically cleave targets after Cys or Thr residues21, we mutated the most likely target cysteine, located in the C-terminal region of Cardif (Cys 508, see Fig. 1a), to alanine (C508A). This construct showed complete resistance to cleavage by NS3-4A (Fig. 4a, right). Wild-type Cardif, but not the C508A mutant form, was also cleaved when the entire HCV polyprotein was inducibly expressed in a U-2 OS-derived tetracycline-regulated cell line (Fig. 4b). Using a recently described in vitro HCV infection system22,23,24, we also observed Cardif cleavage in cells harbouring infectious HCV (Fig. 4c). Upon overexpression in 293T cells, both wild-type and C508A mutant Cardif, but not a Cardif construct lacking the C-terminal cleavage-generated end (Cardif 1–508), triggered an IFN-β response (Fig. 4d). Catalytically active wild-type NS3-4A protease (NS3-4A) potently impaired the ability of wild-type Cardif and RIG-I—but not Cardif (C508A) or IKKɛ—to mediate signalling (Fig. 4d), demonstrating that NS3-4A-mediated cleavage at Cys 508 results in the inactivation of Cardif.
Millions of people are chronically infected with HCV and are at risk of developing liver disease. HCV has evolved an efficient strategy to block a dsRNA-dependent innate immune response, by specifically cleaving and thereby inactivating two adaptor proteins—Trif and Cardif—that have important roles in the two distinct arms of the IFN response mediated by TLR3 and RIG-I, respectively. The potent antiviral activity of BILN 2061, an NS3-4A inhibitor developed for HCV treatment25, was initially explained by its inhibition of the NS3-4A-induced maturation of the HCV polyprotein. In addition, BILN 2061 might prevent Cardif and/or Trif inactivation during infection with HCV, thereby maintaining the innate immune response. Interestingly, a mutation in the Cardif-interacting CARD domain of RIG-I was recently found to allow replication of an HCV replicon in otherwise resistant cells10, supporting an important role for the RIG-I–Cardif pathway in anti-HCV immunity.
A model consistent with our data includes RIG-I (and Helicard) as a crucial sensor for cytoplasmic dsRNA derived from viruses. Upon binding of dsRNA to RIG-I, a conformational change caused by helicase activity could expose its CARD domain, which associates with the CARD domain of Cardif through a homotypic interaction. As a consequence, the C-terminal segment of Cardif exposes binding sites for the IRF3-phosphorylating kinase IKKɛ and the NF-κB-activating kinases IKKα and IKKβ, triggering a strong antiviral IFN-β and inflammatory response. Bearing in mind that HCV (and possibly other viruses that are known to inhibit IFN production16) inactivates the RIG-I–Cardif pathway, identification of therapeutic agents that mimic the CARD-induced conformational change in Cardif may prove a beneficial antiviral strategy.
Note added in proof: Cardif has also recently been identified by two other research groups, and has been named IPS-1 (ref. 31) or MAVS (ref. 32).
Methods
Expression vectors
The full length Cardif cDNA was amplified from an expressed-sequence-tag (EST) (IMAGE clone 5751684) by standard PCR using Pwo polymerase (Roche). Cardif was subsequently cloned into a derivative of pCR3 (Invitrogen), in-frame with an N- or C-terminal VSV or FLAG tag. Cardif CARD (amino acids 1–95), ΔCARD (amino acids 91–540) and C-terminally truncated (amino acids 1–508) coding sequences were amplified by PCR. Mutation of Cys 508 to Ala (C508A) in Cardif was achieved by site-directed mutagenesis with two sequential rounds of PCR. Mouse Irf3 lacking the N-terminal DNA-binding domain (ΔN, amino acids 137–419) was amplified from an EST (IMAGE clone 3666172). The fidelity of all PCR amplifications was confirmed by sequencing. FLAG–IKKα, FLAG–IKKɛ and FLAG–TBK1 were gifts from G. P. Dotto, T. Maniatis, and M. Nakanishi, respectively. FLAG–RIG-I cDNA was provided by T. Fujita. Human TRIF and mouse Helicard (Mda5) expression plasmids have been described11,26. Wild-type pCMVNS3-4A (NS3-4A WT) has been described27, and its catalytically inactive counterpart (NS3-4A*) containing a Ser 139 to Ala mutation will be described elsewhere. NF-κBLuc and IFN-βLuc reporter plasmids were provided by V. Jongeneel and T. Taniguchi, respectively. pISRE-Luc was from Stratagene. The Renilla-luciferase transfection efficiency vector (phRLTK) was purchased from Promega.
PCR with reverse transcription
RT–PCR was performed as described26. Human multiple tissue cDNAs (636742, 636743) were from BD Biosciences. Human primary haematopoietic cells and corresponding cDNAs have been described28. The following primers were used: Cardif, 5′-ACTTCATTGCGGCACTGAGG-3′ and 5′-TCTGGATTCCTTGGGATGGC-3′; β-actin, 5′-GGCATCGTGATGGACTCCG-3′ and 5′-GCTGGAAGGTGGACAGCGA-3′; mouse Thy1 5′-CCATCCAGCATGAGTTCAGCC-3′ and 5′-GCATCCAGGATGTGTTCTGA-3′; mouse Ifnb1 5′-TTCCTGCTGTGCTTCTCCAC-3′ and 5′-GATTCACTACCAGTCCCAGAGTC-3′; mouse Il6 5′-ATGAAGTTCCTCTCTGCAAGAGACT-3′ and 5′-CACTAGGTTTGCCGAGTAGATCTC-3′.
Cell culture conditions
The human embryonic kidney (HEK) 293T cell line, primary mouse embryonic fibroblasts (MEFs) and the hepatoma cell line Huh7.5 (a gift from C.M. Rice) were grown in Dulbecco's modified Eagle's medium (Invitrogen) supplemented with 10% heat-inactivated fetal calf serum. U-2 OS human osteosarcoma-derived cell lines that inducibly express green fluorescent protein (UGFP) or NS3-4A upon tetracycline withdrawal, either alone (UNS3-4A) or in the context of the entire HCV polyprotein (UHCVcon), have been described27,29.
Transfection, immunoprecipitation and immunoblotting
Transfection, immunoprecipitation and immunoblotting assays in 293T cells were performed as previously described26. siRNAs (Ambion) and Poly(I:C) (Invivogen) were also transfected into 293T cells using the calcium-phosphate precipitation technique, at final concentrations of 10 nM (siRNA) or 1 ng ml-1 (Poly(I:C)). MEFs were transfected using Lipofectamine 2000 (Invitrogen) or, in the case of siRNA, using TransIT-TKO (Mirus), according to the manufacturers' instructions. U-2 OS cells were transfected using the calcium-phosphate precipitation technique. Twenty-four hours after transfection, U-2 OS cells were washed twice with PBS and were then cultured for 24 h in the presence (tet+) or absence (tet-) of tetracycline to allow the expression of GFP (UGFP), NS3-4A alone (UNS3-4A) or the entire HCV polyprotein (UHCVcon). Huh7.5 cells were transfected using Effectene (Qiagen), according to the manufacturer's instructions. Anti-FLAG M2 and anti-VSV P5D4 antibodies were from Sigma. Anti-IRF3 (sc-9082) was from Santa Cruz. Anti-NS3 1B6 and anti-NS5A 11H have been previously described27,30. For the HCV infection experiment, a polyclonal anti-NS3 antiserum was used.
Viral infections
Twenty-four hours after transfection, 293T cells were infected for 24 h with Sendai virus (strain H) at a multiplicity of infection (MOI) of 10. Cells were subsequently lysed and assayed for luciferase activity. Thirty hours after transfection with siRNA, primary MEFs were infected for 18 h with VSV at a MOI of 0.1. HCV chimaeric genotype 2a virus, designated Jc1, will be described elsewhere. HCV production was performed as previously described22. Six hours after transfection, Huh7.5 cells were infected for 5 h with cell culture supernatants containing infectious Jc1 particles, cultured for another 60 h and harvested in Laemmli sample buffer for analysis by western blot.
Luciferase reporter assays
Luciferase reporter assays were performed as described previously26.
Analysis of RANTES expression
Forty-eight hours after transfection of 293T cells in 96-well plates, cell supernatants were analysed for human RANTES expression by enzyme-linked immunosorbent assay (ELISA, R&D Systems), according to the manufacturer's instructions. Eighteen hours after infection of MEFs with VSV in 12-well plates, cell supernatants were analysed for murine RANTES expression (murine RANTES ELISA, R&D Systems), according to the manufacturer's instructions.
References
Levy, D. E. & Marie, I. J. RIGging an antiviral defense–it's in the CARDs. Nature Immunol. 5, 699–701 (2004)
Akira, S. & Takeda, K. Toll-like receptor signalling. Nature Rev. Immunol. 4, 499–511 (2004)
Sharma, S. et al. Triggering the interferon antiviral response through an IKK-related pathway. Science 300, 1148–1151 (2003)
Fitzgerald, K. A. et al. IKKɛ and TBK1 are essential components of the IRF3 signalling pathway. Nature Immunol. 4, 491–496 (2003)
Edelmann, K. H. et al. Does Toll-like receptor 3 play a biological role in virus infections? Virology 322, 231–238 (2004)
Andrejeva, J. et al. The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-β promoter. Proc. Natl Acad. Sci. USA 101, 17264–17269 (2004)
Yoneyama, M. et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nature Immunol. 5, 730–737 (2004)
Sun, Y. W. RIG-I, a Human Homolog Gene of RNA Helicase, is Induced by Retinoic Acid During the Differentiation of Acute Promyelocytic Leukemia Cell. Thesis, Shanghai Institute of Hematology, Shanghai Second Medical University (1997)
Kang, D. C. et al. mda-5: An interferon-inducible putative RNA helicase with double-stranded RNA-dependent ATPase activity and melanoma growth-suppressive properties. Proc. Natl Acad. Sci. USA 99, 637–642 (2002)
Sumpter, R. Jr et al. Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I. J. Virol. 79, 2689–2699 (2005)
Kovacsovics, M. et al. Overexpression of Helicard, a CARD-containing helicase cleaved during apoptosis, accelerates DNA degradation. Curr. Biol. 12, 838–843 (2002)
Matsuda, A. et al. Large-scale identification and characterization of human genes that activate NF-κB and MAPK signalling pathways. Oncogene 22, 3307–3318 (2003)
Servant, M. J. et al. Identification of the minimal phosphoacceptor site required for in vivo activation of interferon regulatory factor 3 in response to virus and double-stranded RNA. J. Biol. Chem. 278, 9441–9447 (2003)
Sato, S. et al. Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-κB and IFN-regulatory factor-3, in the Toll-like receptor signalling. J. Immunol. 171, 4304–4310 (2003)
Kato, H. et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity 23, 19–28 (2005)
Conzelmann, K. K. Transcriptional activation of alpha/beta interferon genes: interference by nonsegmented negative-strand RNA viruses. J. Virol. 79, 5241–5248 (2005)
Foy, E. et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease. Science 300, 1145–1148 (2003)
Li, K. et al. Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc. Natl Acad. Sci. USA 102, 2992–2997 (2005)
Foy, E. et al. Control of antiviral defenses through hepatitis C virus disruption of retinoic acid-inducible gene-I signalling. Proc. Natl Acad. Sci. USA 102, 2986–2991 (2005)
Breiman, A. et al. Inhibition of RIG-I-dependent signalling to the interferon pathway during hepatitis C virus expression and restoration of signalling by IKKɛ. J. Virol. 79, 3969–3978 (2005)
Bartenschlager, R., Ahlborn-Laake, L., Yasargil, K., Mous, J. & Jacobsen, H. Substrate determinants for cleavage in cis and in trans by the hepatitis C virus NS3 proteinase. J. Virol. 69, 198–205 (1995)
Wakita, T. et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nature Med. 11, 791–796 (2005)
Zhong, J. et al. Robust hepatitis C virus infection in vitro. Proc. Natl Acad. Sci. USA 102, 9294–9299 (2005)
Lindenbach, B. D. et al. Complete replication of hepatitis C virus in cell culture. Science 309, 623–626 (2005)
Lamarre, D. et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426, 186–189 (2003)
Meylan, E. et al. RIP1 is an essential mediator of Toll-like receptor 3-induced NF-κB activation. Nature Immunol. 5, 503–507 (2004)
Wolk, B. et al. Subcellular localization, stability, and trans-cleavage competence of the hepatitis C virus NS3–NS4A complex expressed in tetracycline-regulated cell lines. J. Virol. 74, 2293–2304 (2000)
Schneider, P. et al. BAFF, a novel ligand of the tumour necrosis factor family, stimulates B cell growth. J. Exp. Med. 189, 1747–1756 (1999)
Schmidt-Mende, J. et al. Determinants for membrane association of the hepatitis C virus RNA-dependent RNA polymerase. J. Biol. Chem. 276, 44052–44063 (2001)
Brass, V. et al. An amino-terminal amphipathic α-helix mediates membrane association of the hepatitis C virus nonstructural protein 5A. J. Biol. Chem. 277, 8130–8139 (2002)
Kawai, T. et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nature Immunol. advance online publication, 28 August 2005 (doi:10.1038/ni1243)
Seth, R. B., Sun, L., Ea, C. K. & Chen, Z. J. Identification and characterization of MAVS, a mitochondrial antiviral signalling protein that activates NF-κB and IRF3. Cell 122, 669–682 (2005)
Acknowledgements
We thank S. Hertig for technical support, and H. Everett, V. Petrilli and O. Donzé for discussions and critical reading of the manuscript. This work was supported by grants from the Swiss National Science Foundation and the Commission of Technology and Innovation (CTI).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The DNA sequence of human Cardif has been deposited in GenBank under accession number DQ181928. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Supplementary information
Supplementary Figure Legends
This section contains legends for Supplementary Figures S1–S3. (DOC 20 kb)
Supplementary Figure S1
This figure is an RT–PCR showing the expression of Cardif in different human cell lines, tissues, and primary cells. (PDF 211 kb)
Supplementary Figure S2
This figure represents a luciferase assay showing that Cardif-induced NF-kB and IRF3 activations are blocked by dominant negative (DN) forms of I-kB and IRF3, respectively. (PDF 18 kb)
Supplementary Figure S3
This figure is a WB showing that siRNAs inhibit the expression of their target genes, namely Cardif, RIG-I, and Trif. (PDF 49 kb)
Rights and permissions
About this article
Cite this article
Meylan, E., Curran, J., Hofmann, K. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172 (2005). https://doi.org/10.1038/nature04193
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature04193
This article is cited by
-
Identification of pigeon mitochondrial antiviral signaling protein (MAVS) and its role in antiviral innate immunity
Archives of Virology (2024)
-
Global trends in research of melanoma differentiation-associated gene 5: a bibliometric analysis from 2002 to 2022
Clinical Rheumatology (2024)
-
Effect of glutamine on the systemic innate immune response in broiler chickens challenged with Salmonella pullorum
BMC Veterinary Research (2023)
-
β-adrenoreceptor-triggered PKA activation negatively regulates the innate antiviral response
Cellular & Molecular Immunology (2023)
-
WDR77 inhibits prion-like aggregation of MAVS to limit antiviral innate immune response
Nature Communications (2023)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.