ZFYVE1 negatively regulates MDA5- but not RIG-I-mediated innate antiviral response

Abstract

The retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), including RIG-I and melanoma differentiation-associated gene 5 (MDA5), sense cytoplasmic viral RNA and initiate innate antiviral responses. How RIG-I and MDA5 are differentially regulated remains enigmatic. In this study, we identified the guanylate-binding protein (GBP) and zinc-finger FYVE domain-containing protein ZFYVE1 as a negative regulator of MDA5-but not RIG-I-mediated innate antiviral responses. ZFYVE1-deficiency promoted MDA5-but not RIG-I-mediated transcription of downstream antiviral genes. Comparing to wild-type mice, Zfyve1 -/mice were significantly protected from lethality induced by encephalomyocarditis virus (EMCV) that is sensed by MDA5, whereas Zfyve1 -/and Zfyve1 +/+ mice were comparable to death induced by vesicular stomatitis virus (VSV) that is sensed by RIG-I. Mechanistically, ZFYVE1 interacted with MDA5 but not RIG-I. ZFYVE1 bound to viral RNA and decreased the ligand binding and oligomerization of MDA5. These findings suggest that ZFYVE1 acts as a specific negative regulator of MDA5-mediated innate immune responses by inhibiting its ligand binding and oligomerization. Author summaryRIG-I and MDA5 are the main cytosolic sensors for invaded viral RNA. How these sensors are differentially regulated is largely unknown. In this study, we identified ZFYVE1 as a specific regulator of MDA5-but not RIG-I-mediated antiviral responses. ZFYVE1deficiency promotes antiviral immune responses and renders the mice less susceptible to EMCV-induced death. ZFYVE1 interacts with MDA5 and viral dsRNA, and inhibits the ligand binding and oligomerization of MDA5. Our study reveals a negative regulatory mechanism for keeping MDA5 inactive in un-infected cells, which contributes to our understanding on how innate antiviral responses are delicately regulated to avoid immune damage. ) to H. B.S, Q.Y., and C.L. The funders had no role in study patterns (PAMPs) are sensed by pathogen recognition receptors (PRRs). The PRRs then trigger a series of signaling events, leading to the induction of type I interferons (IFNs), proinflammatory cytokines and other downstream antiviral effector proteins. These effectors act to inhibit viral replication, clear the infected cells and facilitate adaptive immune responses [1].During viral infection, viral nucleic acids act as important PAMPs. It has been demonstrated that the membrane-associated Toll-like receptor 3 (TLR3) recognizes extracellular and endosomal viral RNA, whereas the cytosolic viral RNA is detected by retinoic acid-inducible gene-I (RIG-I) like receptors (RLRs), including RIG-I and melanoma differentiation-associated gene 5 (MDA5) [2]. Upon binding to their ligands, RIG-I and MDA5 undergo conformational changes and recruit PP1α/γ for their dephosphorylation, which is followed by their K63-linked polyubiquitination by several E3 ubiquitin ligases [3][4][5][6][7]. The RLRs then form longer filaments on viral RNA and then interact with the mitochondrial adaptor protein VISA (also called MAVS, IPS-1, and...

RIG-I triggers a signaling-abortive anti-SARS-CoV-2 defense in human lung cells

“…Immunoblot analysis of whole-cell lysate and immunoprecipitated RIG-I and MDA5 (lower). In addition, encephalomyocarditis virus (EMCV)-derived RNA was specifically detected in MDA5 immunoprecipitates but not RIG-I immunoprecipitates, which were derived from EMCV-infected A549 cells (Extended Data Fig.3e), as previously reported25 . b, RIP assay with A549 RIG-I KO35 cell lysates expressing Flag-tagged deletion mutants of RIG-I prepared after 6 h of infection with SARS-CoV-2 by using anti-Flag antibody.…”

The role of mitophagy during oocyte aging in human, mouse, and Drosophila: implications for oocyte quality and mitochondrial disease

“…DKO, double knockout; H/M/D, human/mouse/Drosophila; ND, no data; OMM, outer mitochondrial membrane. 1 Guo and Yu (2019) ; 2 Steingrimsson et al (1998) ; 3 Baker et al (2014) ; 4 Stocker et al (2003) ; 5 Goorden et al (2011) ; 6 Lieber et al (2019) ; 7 Kuhn et al (2015) ; 8 Cheong et al (2014) ; 9 Kaizuka and Mizushima (2016) ; 10 Gan et al (2006) ; 11 Bertoldo et al (2015) ; 12 Sopko et al (2014) ; 13 Jorgensen et al (2004) ; 14 Wen et al (2017) ; 15 Saitoh et al (2009) ; 16 Zhou et al (2011) ; 17 Nemazanyy et al (2013) ; 18 Gawriluk et al (2011) ; 19 Yue et al (2003) ; 20 Fimia et al (2007) ; 21 Ronkina et al (2007) ; 22 Zhong et al (2020) ; 23 Malhotra et al (2015) ; 24 Sou et al (2008) ; 25 Tsukamoto et al (2008 b ) ; 26 Kuma et al (2004) ; 27 Song et al (2015) ; 28 Komatsu et al (2005) ; 29 Saitoh et al (2008) ; 30 Cann et al (2008) ; 31 O’Sullivan et al (2005) ; 32 Sasai et al (2017) ; 33 Skarnes ...…”

USP14: Structure, Function, and Target Inhibition

“…Viral infections stimulate the innate immune response, including the inflammatory response, which is a crucial biochemical reaction against the invasion by microbial pathogens ( Figure 5 ) ( Shrivastava et al, 2016 ). Retinoic acid-inducible gene I (RIG-I) is an essential recognition receptor of the innate immune system that detects RNA viruses ( Zhong et al, 2020 ). Genetic knockdown or pharmacological inhibition of USP14 was demonstrated to significantly promote the production of proinflammatory cytokines in macrophages of mice infected by vesicular stomatitis virus (VSV).…”