iRhom2 is essential for innate immunity to RNA virus by antagonizing ER- and mitochondria-associated degradation of VISA

Luo, Weiwei; Li, Shu; Li, Chen; Zheng, Zhou-Qin; Cao, Pan; Tong, Zhen; Lian, Huan; Wang, Suyun; Shu, Hong‐Bing; Wang, Yan-Yi

doi:10.1371/journal.ppat.1006693

Cited by 41 publications

(37 citation statements)

References 37 publications

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“…These include OTUD4, PCBP2, RNF5, Tetherin, NS1 of Duck Tembusu Virus, iRhom2, ECSIT and GP73. 27,29,34,36,[52][53][54] The TM domain of MAVS is also crucial for its oligomerization after viral infection. 11,55 Interestingly, the truncated MAVS(aa361-540) used in this study is sufficient to activate ISRE or NF-κB in reporter assays.…”

Section: Discussionmentioning

confidence: 99%

“…34 More recently, it has been reported that OTUD1 induces the upregulation of Smurf1 to promote ubiquitination and proteasomal degradation of MAVS, 35 whereas iRhom2 promotes ubiquitination and degradation of RNF5 and MARCH5 to antagonize MAVS degradation. 36 However, the process whereby MAVS is deubiquitinated is unclear and whether and how its deubiquitination might regulate the innate antiviral responses remain to be investigated.…”

Section: Introductionmentioning

confidence: 99%

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Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS

Liuyu

et al. 2018

Cell Res

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The activity and stability of the adapter protein MAVS (also known as VISA, Cardif and IPS-1), which critically mediates cellular antiviral responses, are extensively regulated by ubiquitination. However, the process whereby MAVS is deubiquitinated is unclear.Here, we report that the ovarian tumor family deubiquitinase 4 (OTUD4) targets MAVS for deubiquitination. Viral infection leads to the IRF3/7-dependent upregulation of OTUD4 which interacts with MAVS to remove K48-linked polyubiquitin chains, thereby maintaining MAVS stability and promoting innate antiviral signaling. Knockout or knockdown of OTUD4 impairs RNA virus-triggered activation of IRF3 and NF-κB, expression of their downstream target genes, and potentiates VSV replication in vitro and in vivo. Consistently, Cre-ER Otud4 fl/fl or Lyz2-Cre Otud4 fl/fl mice produce decreased levels of type I interferons and proinflammatory cytokines and exhibit increased sensitivity to VSV infection compared to their control littermates. In addition, reconstitution of MAVS into OTUD4-deficient cells restores virus-induced expression of downstream genes and cellular antiviral responses. Together, our findings uncover an essential role of OTUD4 in virus-triggered signaling and contribute to the understanding of deubiquitination-mediated regulation of innate antiviral responses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS

Liuyu

et al. 2018

Cell Res

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“…HFFs were provided by Dr. Min-Hua Luo (Wuhan Institute of Virology, CAS). SeV (Cantell strain), EMCV (BJC3 Strain) and VSV (Indiana Strain) were previously described [28,30].…”

Section: Reagents Antibodies Cells and Virusesmentioning

confidence: 99%

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

Zhong

Zang

et al. 2020

PLoS Pathog

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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...

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“…In agreement with findings in Sting ‐deficient mice, iRhom2 ‐deficient mice are significantly less resistant to HSV‐1 infection. In a follow‐up study, the authors also invoke a role for iRhom2 in innate immune responses to the RNA virus VSV by mediating the protein stability of the central adaptor mitochondrial antiviral signaling protein (MAVS) . By mediating the auto‐ubiquitination and degradation of the E3 ubiquitin ligase ring finger protein (RNF) 5, which then prevents the assembly of MAVS‐RNF5 complexes, iRhom2 antagonizes ER‐associated degradation of MAVS.…”

Section: Biological Functions Of Irhomsmentioning

confidence: 99%

“…Similar to rhomboids, iRhom2 and possibly iRhom1 also require transmembrane interactions with their interacting binding partners for their biological functions . Targeting membrane protein interactions offer significant challenges for designing anti‐TMD directed therapeutics.…”

Section: Irhoms As Targets For Drug Developmentmentioning

confidence: 99%

Novel functions of inactive rhomboid proteins in immunity and disease

Geesala

Issuree

Maretzky

2019

Journal of Leukocyte Biology

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iRhoms are related to a family of intramembrane serine proteinases called rhomboids but lack proteolytic activity. In mammals, there are two iRhoms, iRhom1 and iRhom2, which have similar domain structures and overlapping specificities as well as distinctive functions. These catalytically inactive rhomboids are essential regulators for the maturation and trafficking of the disintegrin metalloprotease ADAM17 from the endoplasmic reticulum to the cell surface, and are required for the cleavage and release of a variety of membrane-associated proteins, including the IL-6 receptor, L-selectin, TNF, and EGFR ligands. iRhom2-dependent regulation of ADAM17 function has been recently implicated in the development and progression of several autoimmune diseases including rheumatoid arthritis, lupus nephritis, as well as hemophilic arthropathy. In this review, we discuss our current understanding of iRhom biology, their implications in autoimmune pathologies, and their potential as therapeutic targets. K E Y W O R D Sa disintegrin and metalloprotease 17 (ADAM17), epidermal growth factor receptor (EGFR), inactive rhomboid 1 (iRHOM1), inactive rhomboid 2 (iRHOM2), rhomboid 5 homolog 1 (RHBDF1), rhomboid 5 homolog 2 (RHBDF2), tumor necrosis factor (TNF) 1 L-selectin from leukocytes and has key roles in their recruitment to sites of inflammation. 10 Moreover, ADAM17 has a wide range of different substrates, 11 including the IL-6 receptor (IL6R), which has important roles in IL6R-dependent pathologies such as multiple myeloma, prostate cancer, and RA. 12,13 The rhomboid 5 homolog proteins iRhom1 and iRhom2 (also known as RHBDF1 and RHBDF2) are proteolytically inactive members of the rhomboid family and act as key regulators of ADAM17-dependent

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iRhom2 is essential for innate immunity to RNA virus by antagonizing ER- and mitochondria-associated degradation of VISA

Cited by 41 publications

References 37 publications

Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS

Induction of OTUD4 by viral infection promotes antiviral responses through deubiquitinating and stabilizing MAVS

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

Novel functions of inactive rhomboid proteins in immunity and disease

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