Phosphatase PP4 Negatively Regulates Type I IFN Production and Antiviral Innate Immunity by Dephosphorylating and Deactivating TBK1

Many viral proteases mediate the evasion of antiviral innate immunity by cleaving adapter proteins in the interferon (IFN) induction pathway. Host proteases are also involved in innate immunity and inflammation. Here, we report that the transmembrane protease hepsin (also known as TMPRSS1), which is predominantly present in hepatocytes, inhibited the induction of type I IFN during viral infections. Knocking out hepsin in mouse embryonic fibroblasts (MEFs) increased the viral infection–induced expression of Ifnb1, an Ifnb1 promoter reporter, and an IFN-sensitive response element promoter reporter. Ectopic expression of hepsin in cultured human hepatocytes and HEK293T cells suppressed the induction of IFNβ during viral infections by reducing the abundance of STING. These effects depended on the protease activity of hepsin. We identified a putative hepsin target site in STING and showed that mutating this site protected STING from hepsin-mediated cleavage. In addition to hepatocytes, several hepsin-producing prostate cancer cell lines showed reduced STING-mediated type I IFN induction and responses. These results reveal a role for hepsin in suppressing STING-mediated type I IFN induction, which may contribute to the vulnerability of hepatocytes to chronic viral infections.

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Herpes Simplex Virus 1 UL36USP Antagonizes Type I Interferon-Mediated Antiviral Innate Immunity

Journal of Virology ◽

10.1128/jvi.01161-18 ◽

2018 ◽

Vol 92 (19) ◽

Cited By ~ 14

Author(s):

Hui Yuan ◽

Jia You ◽

Hongjuan You ◽

Chunfu Zheng

Keyword(s):

Innate Immune ◽

Type I ◽

Type I Ifn ◽

Herpes Simplex Virus 1 ◽

Type I Ifns ◽

Specific Protease ◽

Ubiquitin Specific Protease ◽

Simplex Virus ◽

Antiviral Innate Immunity ◽

Hsv 1

ABSTRACT Type I interferons (IFNs), as major components of the innate immune system, play a vital role in host resistance to a variety of pathogens. Canonical signaling mediated by type I IFNs activates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway through binding to the IFN-α/β receptor (IFNAR), resulting in transcription of IFN-stimulated genes (ISGs). However, viruses have evolved multiple strategies to evade this process. Here, we report that herpes simplex virus 1 (HSV-1) ubiquitin-specific protease (UL36USP) abrogates the type I IFN-mediated signaling pathway independent of its deubiquitinase (DUB) activity. In this study, ectopically expressed UL36USP inhibited IFN-β-induced activation of ISRE promoter and transcription of ISGs, and overexpression of UL36USP lacking DUB activity did not influence this effect. Furthermore, UL36USP was demonstrated to antagonize IFN-β-induced activation of JAKs and STATs via specifically binding to the IFNAR2 subunit and blocking the interaction between JAK1 and IFNAR2. More importantly, knockdown of HSV-1 UL36USP restored the formation of JAK1-IFNAR2 complex. These findings underline the roles of UL36USP-IFNAR2 interaction in counteracting the type I IFN-mediated signaling pathway and reveal a novel evasion mechanism of antiviral innate immunity by HSV-1. IMPORTANCE Type I IFNs mediate transcription of numerous antiviral genes, creating a remarkable antiviral state in the host. Viruses have evolved various mechanisms to evade this response. Our results indicated that HSV-1 encodes a ubiquitin-specific protease (UL36USP) as an antagonist to subvert type I IFN-mediated signaling. UL36USP was identified to significantly inhibit IFN-β-induced signaling independent of its deubiquitinase (DUB) activity. The underlying mechanism of UL36USP antagonizing type I IFN-mediated signaling was to specifically bind with IFNAR2 and disassociate JAK1 from IFNAR2. For the first time, we identify UL36USP as a crucial suppressor for HSV-1 to evade type I IFN-mediated signaling. Our findings also provide new insights into the innate immune evasion by HSV-1 and will facilitate our understanding of host-virus interplay.

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A Tug of War: DNA-Sensing Antiviral Innate Immunity and Herpes Simplex Virus Type I Infection

Frontiers in Microbiology ◽

10.3389/fmicb.2019.02627 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 7

Author(s):

Yingying Lin ◽

Chunfu Zheng

Keyword(s):

Innate Immunity ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Type I ◽

Dna Sensing ◽

Simplex Virus ◽

Antiviral Innate Immunity

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Type I IFN Receptor Regulates Neutrophil Functions and Innate Immunity toLeishmaniaParasites

The Journal of Immunology ◽

10.4049/jimmunol.0903273 ◽

2010 ◽

Vol 184 (12) ◽

pp. 7047-7056 ◽

Cited By ~ 56

Author(s):

Lijun Xin ◽

Diego A. Vargas-Inchaustegui ◽

Sharon S. Raimer ◽

Brent C. Kelly ◽

Jiping Hu ◽

...

Keyword(s):

Innate Immunity ◽

Type I ◽

Type I Ifn

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DDX3X Links NLRP11 to the Regulation of Type I Interferon Responses and NLRP3 Inflammasome Activation

Frontiers in Immunology ◽

10.3389/fimmu.2021.653883 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ioannis Kienes ◽

Sarah Bauer ◽

Clarissa Gottschild ◽

Nora Mirza ◽

Jens Pfannstiel ◽

...

Keyword(s):

Innate Immunity ◽

Nlrp3 Inflammasome ◽

Inflammatory Cytokine ◽

Inflammasome Activation ◽

Type I ◽

Dependent Manner ◽

Type I Ifn ◽

Central Target ◽

Nlrp3 Inflammasome Activation ◽

Lrr Domain

Tight regulation of inflammatory cytokine and interferon (IFN) production in innate immunity is pivotal for optimal control of pathogens and avoidance of immunopathology. The human Nod-like receptor (NLR) NLRP11 has been shown to regulate type I IFN and pro-inflammatory cytokine responses. Here, we identified the ATP-dependent RNA helicase DDX3X as a novel binding partner of NLRP11, using co-immunoprecipitation and LC-MS/MS. DDX3X is known to enhance type I IFN responses and NLRP3 inflammasome activation. We demonstrate that NLRP11 can abolish IKKϵ-mediated phosphorylation of DDX3X, resulting in lower type I IFN induction upon viral infection. These effects were dependent on the LRR domain of NLRP11 that we mapped as the interaction domain for DDX3X. In addition, NLRP11 also suppressed NLRP3-mediated caspase-1 activation in an LRR domain-dependent manner, suggesting that NLRP11 might sequester DDX3X and prevent it from promoting NLRP3-induced inflammasome activation. Taken together, our data revealed DDX3X as a central target of NLRP11, which can mediate the effects of NLRP11 on type I IFN induction as well as NLRP3 inflammasome activation. This expands our knowledge of the molecular mechanisms underlying NLRP11 function in innate immunity and suggests that both NLRP11 and DDX3X might be promising targets for modulation of innate immune responses.

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Swine Acute Diarrhea Syndrome Coronavirus Nucleocapsid Protein Antagonizes Interferon-β Production via Blocking the Interaction Between TRAF3 and TBK1

Frontiers in Immunology ◽

10.3389/fimmu.2021.573078 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhihai Zhou ◽

Yuan Sun ◽

Jingya Xu ◽

Xiaoyu Tang ◽

Ling Zhou ◽

...

Keyword(s):

Innate Immunity ◽

Acute Diarrhea ◽

Nuclear Translocation ◽

Sendai Virus ◽

Type I ◽

Innate Immune Responses ◽

N Protein ◽

Antiviral Innate Immunity ◽

Diarrhea Syndrome

Swine acute diarrhea syndrome coronavirus (SADS-CoV), first discovered in 2017, is a porcine enteric coronavirus that can cause acute diarrhea syndrome (SADS) in piglets. Here, we studied the role of SADS-CoV nucleocapsid (N) protein in innate immunity. Our results showed that SADS-CoV N protein could inhibit type I interferon (IFN) production mediated by Sendai virus (Sev) and could block the phosphorylation and nuclear translocation of interferon regulatory factor 3 (IRF3). Simultaneously, the IFN-β promoter activity mediated by TANK binding kinase 1 (TBK1) or its upstream molecules in the RLRs signal pathway was inhibited by SADS-CoV N protein. Further investigations revealed that SADS-CoV N protein could counteract interaction between TNF receptor-associated factor 3 (TRAF3) and TBK1, which led to reduced TBK1 activation and IFN-β production. Our study is the first report of the interaction between SADS-CoV N protein and the host antiviral innate immune responses, and the mechanism utilized by SADS-CoV N protein provides a new insight of coronaviruses evading host antiviral innate immunity.

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Virus Caused Imbalance of Type I IFN Responses and Inflammation in COVID-19

Frontiers in Immunology ◽

10.3389/fimmu.2021.633769 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jintao Zhang ◽

Chunyuan Zhao ◽

Wei Zhao

Keyword(s):

Innate Immunity ◽

Innate Immune System ◽

Innate Immune ◽

Type I Interferons ◽

Type I ◽

Type I Ifn ◽

Antiviral Responses ◽

Public Health Challenges ◽

Host Innate Immunity ◽

Efficient Elimination

The global expansion of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as one of the greatest public health challenges and imposes a great threat to human health. Innate immunity plays vital roles in eliminating viruses through initiating type I interferons (IFNs)-dependent antiviral responses and inducing inflammation. Therefore, optimal activation of innate immunity and balanced type I IFN responses and inflammation are beneficial for efficient elimination of invading viruses. However, SARS-CoV-2 manipulates the host’s innate immune system by multiple mechanisms, leading to aberrant type I IFN responses and excessive inflammation. In this review, we will emphasize the recent advances in the understanding of the crosstalk between host innate immunity and SARS-CoV-2 to explain the imbalance between inflammation and type I IFN responses caused by viral infection, and explore potential therapeutic targets for COVID-19.

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LncRNAMalat1inhibition of TDP43 cleavage suppresses IRF3-initiated antiviral innate immunity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2003932117 ◽

2020 ◽

Vol 117 (38) ◽

pp. 23695-23706 ◽

Cited By ~ 1

Author(s):

Wei Liu ◽

Ziqiao Wang ◽

Lun Liu ◽

Zongheng Yang ◽

Shuo Liu ◽

...

Keyword(s):

Viral Infection ◽

Lupus Erythematosus ◽

Mononuclear Cells ◽

Negative Regulator ◽

Type I ◽

Type I Ifn ◽

Peripheral Blood Mononuclear ◽

Interactive Network ◽

Antiviral Innate Immunity

Long noncoding RNAs (lncRNAs) involved in the regulation of antiviral innate immune responses need to be further identified. By functionally screening the lncRNAs in macrophages, here we identified lncRNAMalat1, abundant in the nucleus but significantly down-regulated after viral infection, as a negative regulator of antiviral type I IFN (IFN-I) production.Malat1directly bound to the transactive response DNA-binding protein (TDP43) in the nucleus and prevented activation of TDP43 by blocking the activated caspase-3-mediated TDP43 cleavage to TDP35. The cleaved TDP35 increased the nuclear IRF3 protein level by binding and degradingRbck1pre-mRNA to prevent IRF3 proteasomal degradation upon viral infection, thus selectively promoting antiviral IFN-I production. Deficiency ofMalat1enhanced antiviral innate responses in vivo, accompanying the increased IFN-I production and reduced viral burden. Importantly, the reducedMALAT1, augmented IRF3, and increasedIFNAmRNA were found in peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) patients. Therefore, the down-regulation ofMALAT1in virus-infected cells or in human cells from autoimmune diseases will increase host resistance against viral infection or lead to autoinflammatory interferonopathies via the increased type I IFN production. Our results demonstrate that the nuclearMalat1suppresses antiviral innate responses by targeting TDP43 activation via RNA-RBP interactive network, adding insight to the molecular regulation of innate responses and autoimmune pathogenesis.

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