scholarly journals Phosphorylation of the selective autophagy receptor TAX1BP1 by canonical and noncanonical IκB kinases promotes its lysosomal localization and clearance of MAVS aggregates

2021 ◽  
Author(s):  
Young Bong Choi ◽  
Jiawen Zhang ◽  
Mai Tram Vo ◽  
Jesse White ◽  
Chaoxia He ◽  
...  
Keyword(s):  
Virus Infection ◽  
Rna Virus ◽  
Critical Role ◽  
Selective Autophagy ◽  
The Core ◽  
Data Support ◽  
Iκb Kinase

TAX1BP1 is a selective autophagy receptor which inhibits NF-κB and RIG-I-like receptor (RLR) signaling to prevent excessive inflammation and maintain homeostasis. Selective autophagy receptors such as p62/SQSTM1 and OPTN are phosphorylated by the noncanonical IκB kinase TBK1 to stimulate their selective autophagy function. However, it is unknown if TAX1BP1 is regulated by TBK1 or other kinases under basal conditions or during RNA virus infection. Here, we found that the noncanonical IκB kinases TBK1 and IKKi phosphorylate TAX1BP1 to regulate its basal turnover, whereas the canonical IκB kinase IKKα and the core autophagy factor ATG9 play essential roles in RNA virus-mediated TAX1BP1 autophagosomal degradation. TAX1BP1 phosphorylation by canonical and noncanonical IκB kinases promotes its localization to lysosomes resulting in its degradation. Furthermore, TAX1BP1 plays a critical role in the clearance of MAVS aggregates, and phosphorylation of TAX1BP1 augments its MAVS aggrephagy function. Together, our data support a model whereby IκB kinases license TAX1BP1 selective autophagy function to inhibit MAVS and RLR signaling.

scholarly journals Inhibition of Antiviral Innate Immunity by Avibirnavirus VP3 via Blocking TBK1-TRAF3 Complex Formation and IRF3 Activation

mSystems ◽  
2021 ◽  
Vol 6 (3) ◽  
Author(s):  
Tingjuan Deng ◽  
Boli Hu ◽  
Xingbo Wang ◽  
Lulu Lin ◽  
Jianwei Zhou ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Virus Infection ◽  
Complex Formation ◽  
Rna Virus ◽  
Critical Role ◽  
Type I ◽  
Antiviral Immune Response ◽  
Critical Residue ◽  
Irf3 Activation

ABSTRACT The host innate immune system develops various strategies to antagonize virus infection, and the pathogen subverts or evades host innate immunity for self-replication. In the present study, we discovered that Avibirnavirus infectious bursal disease virus (IBDV) VP3 protein significantly inhibits MDA5-induced beta interferon (IFN-β) expression by blocking IRF3 activation. Binding domain mapping showed that the CC1 domain of VP3 and the residue lysine-155 of tumor necrosis factor receptor-associated factor 3 (TRAF3) are essential for the interaction. Furthermore, we found that the CC1 domain was required for VP3 to downregulate MDA5-mediated IFN-β production. A ubiquitination assay showed that lysine-155 of TRAF3 was the critical residue for K33-linked polyubiquitination, which contributes to the formation of a TRAF3-TBK1 complex. Subsequently, we revealed that VP3 blocked TRAF3-TBK1 complex formation through reducing K33-linked polyubiquitination of lysine-155 on TRAF3. Taken together, our data reveal that VP3 inhibits MDA5-dependent IRF3-mediated signaling via blocking TRAF3-TBK1 complex formation, which improves our understanding of the interplay between RNA virus infection and the innate host antiviral immune response. IMPORTANCE Type I interferon plays a critical role in the host response against virus infection, including Avibirnavirus. However, many viruses have developed multiple strategies to antagonize the innate host antiviral immune response during coevolution with the host. In this study, we first identified that K33-linked polyubiquitination of lysine-155 of TRAF3 enhances the interaction with TBK1, which positively regulates the host IFN immune response. Meanwhile, we discovered that the interaction of the CC1 domain of the Avibirnavirus VP3 protein and the residue lysine-155 of TRAF3 reduced the K33-linked polyubiquitination of TRAF3 and blocked the formation of the TRAF3-TBK1 complex, which contributed to the downregulation of host IFN signaling, supporting viral replication.

scholarly journals Critical Role of Interferon-α Constitutively Produced in Human Hepatocytes in Response to RNA Virus Infection

PLoS ONE ◽  
2014 ◽  
Vol 9 (2) ◽  
pp. e89869 ◽  
Author(s):  
Yoji Tsugawa ◽  
Hiroki Kato ◽  
Takashi Fujita ◽  
Kunitada Shimotohno ◽  
Makoto Hijikata
Keyword(s):  
Virus Infection ◽  
Rna Virus ◽  
Critical Role ◽  
Human Hepatocytes ◽  
Interferon Α

scholarly journals Autophagic feedback-mediated degradation of IKKα requires CHK1- and p300/CBP-dependent acetylation of p53

2020 ◽  
Vol 133 (22) ◽  
pp. jcs246868
Author(s):  
Xiuduan Xu ◽  
Chongchong Zhang ◽  
Huan Xu ◽  
Lin Wu ◽  
Meiru Hu ◽  
...  
Keyword(s):  
Complex Formation ◽  
Feedback Loop ◽  
Hepatoma Cell ◽  
Critical Role ◽  
Human Hepatoma Cells ◽  
Catalytic Subunits ◽  
Selective Autophagy ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Autophagic Degradation

ABSTRACTIn our previous report, we demonstrated that one of the catalytic subunits of the IκB kinase (IKK) complex, IKKα (encoded by CHUK), performs an NF-κB-independent cytoprotective role in human hepatoma cells under the treatment of the anti-tumor therapeutic reagent arsenite. IKKα triggers its own degradation, as a feedback loop, by activating p53-dependent autophagy, and therefore contributes substantially to hepatoma cell apoptosis induced by arsenite. Interestingly, IKKα is unable to interact with p53 directly but plays a critical role in mediating p53 phosphorylation (at Ser15) by promoting CHK1 activation and CHK1–p53 complex formation. In the current study, we found that p53 acetylation (at Lys373 and/or Lys382) was also critical for the induction of autophagy and the autophagic degradation of IKKα during the arsenite response. Furthermore, IKKα was involved in p53 acetylation through interaction with the acetyltransferases for p53, p300 (also known as EP300) and CBP (also known as CREBBP) (collectively p300/CBP), inducing CHK1-dependent p300/CBP activation and promoting p300–p53 or CBP–p53 complex formation. Therefore, taken together with the previous report, we conclude that both IKKα- and CHK1-dependent p53 phosphorylation and acetylation contribute to mediating selective autophagy feedback degradation of IKKα during the arsenite-induced proapoptotic responses.

scholarly journals Control of antiviral innate immune response by protein geranylgeranylation

2019 ◽  
Vol 5 (5) ◽  
pp. eaav7999 ◽  
Author(s):  
Shigao Yang ◽  
Alfred T. Harding ◽  
Catherine Sweeney ◽  
David Miao ◽  
Gregory Swan ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Innate Immune Response ◽  
Influenza A ◽  
Rna Virus ◽  
Critical Role ◽  
Innate Immune ◽  
Junction Protein ◽  
Mitochondrial Antiviral Signaling ◽  
Destructive Inflammation

The mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS’ interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIPL to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.

scholarly journals A Critical Role for STING Signaling in Limiting Pathogenesis of Chikungunya Virus

2020 ◽  
Author(s):  
Tingting Geng ◽  
Tao Lin ◽  
Duomeng Yang ◽  
Andrew G Harrison ◽  
Anthony T Vella ◽  
...  
Keyword(s):  
Virus Infection ◽  
Chikungunya Virus ◽  
Immune Cell ◽  
Rna Virus ◽  
Critical Role ◽  
Joint Damage ◽  
Interferon Γ ◽  
Type I ◽  
Dna And Rna ◽  
Sting Pathway

Abstract The stimulator of interferon gene (STING) pathway controls both DNA and RNA virus infection. STING is essential for induction of innate immune responses during DNA virus infection, while its mechanism against RNA virus remains largely elusive. We show that STING signaling is crucial for restricting chikungunya virus infection and arthritis pathogenesis. Sting-deficient mice (Stinggt/gt) had elevated viremia throughout the viremic stage and viral burden in feet transiently, with a normal type I IFN response. Stinggt/gt mice presented much greater foot swelling, joint damage, and immune cell infiltration than wild-type mice. Intriguingly, expression of interferon-γ and Cxcl10 was continuously upregulated by approximately 7 to 10-fold and further elevated in Stinggt/gt mice synchronously with arthritis progression. However, expression of chemoattractants for and activators of neutrophils, Cxcl5, Cxcl7, and Cxcr2 was suppressed in Stinggt/gt joints. These results demonstrate that STING deficiency leads to an aberrant chemokine response that promotes pathogenesis of CHIKV arthritis.

scholarly journals A plant RNA virus activates selective autophagy in a UPR‐dependent manner to promote virus infection

2020 ◽  
Vol 228 (2) ◽  
pp. 622-639 ◽  
Author(s):  
Fangfang Li ◽  
Changwei Zhang ◽  
Ziwei Tang ◽  
Lingrui Zhang ◽  
Zhaoji Dai ◽  
...  
Keyword(s):  
Virus Infection ◽  
Rna Virus ◽  
Dependent Manner ◽  
Selective Autophagy

scholarly journals DDX1 from Cherry valley duck mediates signaling pathways and anti-NDRV activity

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Huihui Zhang ◽  
Xingdong Song ◽  
Tianxu Li ◽  
Jinchao Wang ◽  
Bin Xing ◽  
...  
Keyword(s):  
Virus Infection ◽  
Rna Virus ◽  
Critical Role ◽  
Innate Immune ◽  
Economic Losses ◽  
Dead Box ◽  
Activation Of Transcription ◽  
New Ideas ◽  
And Control

AbstractNovel duck reovirus (NDRV) causes severe economic losses to the duck industry, which is characterized by hemorrhagic spots and necrotic foci of the livers and spleens. DEAD-box helicase 1 (DDX1) plays a critical role in the innate immune system against viral infection. However, the role of duck DDX1 (duDDX1) in anti-RNA virus infection, especially in the anti-NDRV infection, has yet to be elucidated. In the present study, the full-length cDNA of duDDX1 (2223 bp encode 740 amino acids) was firstly cloned from the spleen of healthy Cherry valley ducks, and the phylogenetic tree indicated that the duDDX1 has the closest relationship with Anas platyrhynchos in the bird branch. The duDDX1 mRNA was widely distributed in all tested tissues, especially in the duodenum, liver, and spleen. Overexpression of duDDX1 in primary duck embryo fibroblast (DEF) cells triggered the activation of transcription factors IRF-7 and NF-κB, as well as IFN-β expression, and the expression of the Toll-like receptors (TLR2, TLR3, and TLR4) was significantly increased. Importantly, after overexpressing or knocking down duDDX1 and infecting NDRV in DEF cells, duDDX1 inhibits the replication of NDRV virus and also regulates the expression of pattern recognition receptors and cytokines. This indicates that duDDX1 may play an important role in the innate immune response of ducks to NDRV. Collectively, we first cloned DDX1 from ducks and analyzed its biological functions. Secondly, we proved that duck DDX1 participates in anti-NDRV infection, and innovated new ideas for the prevention and control of duck virus infection.

Sign in / Sign up

Export Citation Format

Share Document