TRIM32-TAX1BP1-dependent selective autophagic degradation of TRIF negatively regulates TLR3/4-mediated innate immune responses

Yang, Qing; Liu, Tiantian; Lin, Heng; Zhang, Man; Jin, Wei; Luo, Weiwei; Hu, Yunhong; Zhong, Bo; Hu, Mingming; Shu, Hong‐Bing

doi:10.1371/journal.ppat.1006600

Cited by 91 publications

(79 citation statements)

References 42 publications

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“…Expression plasmids for HA-tagged, FLAG-tagged UL44 and its truncation mutants were constructed by standard molecular biology techniques. Expression plasmids for FLAG-tagged IRF3, TBK1, p65, p50, IRF7, MITA, and IB␣ and the ISRE, IFN-␤, and NF-B promoter reporter plasmids have been described previously (8,(54)(55)(56).…”

Section: Methodsmentioning

confidence: 99%

Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral Immune Responses by Suppressing IRF3- and NF-κB-Mediated Transcription

Zou

et al. 2019

J Virol

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Innate immunity is the first line of host defense against viral invasion. The induction of type I interferons (IFNs) and inflammatory cytokines is essential to host antiviral immune responses, which are also key targets of viral immune evasion. Human cytomegalovirus (HCMV) can establish long-term latent infections, in which immune evasion is a pivotal step. In this study, we identified HCMV protein UL44, a DNA polymerase processivity factor, as an inhibitor of the interferon regulatory factor 3 (IRF3)-and NF-B-dependent antiviral response. Ectopic expression of UL44 inhibited HCMV-triggered induction of downstream effector genes and enhanced viral replication. Conversely, knockdown of UL44 potentiated HCMV-triggered induction of downstream antiviral genes. UL44 interacted with IRF3 and p65, and it inhibited the binding of IRF3 and NF-B to the promoters of their downstream antiviral genes. These findings reveal an important mechanism of immune evasion by HCMV at the transcriptional level. IMPORTANCE Induction of type I IFNs and inflammatory cytokines plays pivotal roles in host antiviral innate immune responses. Viruses have evolved various mechanisms to interfere with these processes. HCMV causes severe ailments in immunodeficient populations and is a major cause of birth defects. It has been shown that HCMV antagonizes host innate immune defenses, which is important for establishing immune evasion and latent infection. In this study, we identified the HCMV DNA polymerase subunit UL44 as a suppressor of antiviral innate immune responses. Overexpression of UL44 impaired HCMV-triggered induction of type I IFNs and other antiviral genes and thus potentiated viral replication, whereas UL44 deficiency showed opposite effects. Mechanistic studies indicated that UL44 acts by inhibiting the binding of IRF3 and NF-B to the promoters of downstream antiviral genes. These findings defined an important mechanism of HCMV immune evasion at the transcriptional level, which may provide a therapeutic target for the treatment of HCMV infection.

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Section: Methodsmentioning

confidence: 99%

Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral Immune Responses by Suppressing IRF3- and NF-κB-Mediated Transcription

Zou

et al. 2019

J Virol

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“…Primary MLFs were prepared from approximately 6-to 8-week-old mice as described [34]. The lungs were minced and digested in calcium and magnesium free HBSS containing 10 μg/ ml type II collagenase and 20 μg/ml DNase I at 37˚C for 3 h with shaking.…”

Section: Preparation Of Mlfsmentioning

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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“…Next, we observed a sustained interferon gene response signature (IRG) in Crohn's disease and ulcerative colitis patients who failed to respond to anti-TNF therapy. Cumulatively, we and others [14,15] have demonstrated that inhibiting autophagy results in an aberrant pro-inflammatory response via sustained activation of specific signals, providing molecular clues to the type of innate immunity elicited by defects in this critical immunoregulatory pathway.…”

mentioning

confidence: 93%

Controlling inflammation by selective autophagy

Lim¹,

Murthy²

2018

Cell Death Differ

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TRIM32-TAX1BP1-dependent selective autophagic degradation of TRIF negatively regulates TLR3/4-mediated innate immune responses

Cited by 91 publications

References 42 publications

Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral Immune Responses by Suppressing IRF3- and NF-κB-Mediated Transcription

Human Cytomegalovirus DNA Polymerase Subunit UL44 Antagonizes Antiviral Immune Responses by Suppressing IRF3- and NF-κB-Mediated Transcription

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

Controlling inflammation by selective autophagy

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