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      p38 inhibition provides anti–DNA virus immunity by regulation of USP21 phosphorylation and STING activation

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          Abstract

          Chen et al. show that USP21 is a deubiquitinating enzyme for the adaptor protein STING and that it negatively regulates the DNA virus–induced production of type I interferons. HSV-1 infection recruited USP21 to STING at a late stage by p38-mediated phosphorylation of USP21 at Ser538.

          Abstract

          Stimulator of IFN genes (STING) is a central adaptor protein that mediates the innate immune responses to DNA virus infection. Although ubiquitination is essential for STING function, how the ubiquitination/deubiquitination system is regulated by virus infection to control STING activity remains unknown. In this study, we found that USP21 is an important deubiquitinating enzyme for STING and that it negatively regulates the DNA virus–induced production of type I interferons by hydrolyzing K27/63-linked polyubiquitin chain on STING. HSV-1 infection recruited USP21 to STING at late stage by p38-mediated phosphorylation of USP21 at Ser538. Inhibition of p38 MAPK enhanced the production of IFNs in response to virus infection and protected mice from lethal HSV-1 infection. Thus, our study reveals a critical role of p38-mediated USP21 phosphorylation in regulating STING-mediated antiviral functions and identifies p38-USP21 axis as an important pathway that DNA virus adopts to avoid innate immunity responses.

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          ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization.

          Xiang Zhou, Yi Feng Zhou, Zhonghe Zhai … (2009)
          We report here the identification and characterization of a protein, ERIS, an endoplasmic reticulum (ER) IFN stimulator, which is a strong type I IFN stimulator and plays a pivotal role in response to both non-self-cytosolic RNA and dsDNA. ERIS (also known as STING or MITA) resided exclusively on ER membrane. The ER retention/retrieval sequence RIR was found to be critical to retain the protein on ER membrane and to maintain its integrity. ERIS was dimerized on innate immune challenges. Coumermycin-induced ERIS dimerization led to strong and fast IFN induction, suggesting that dimerization of ERIS was critical for self-activation and subsequent downstream signaling.
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            Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response.

            Tatsuya Saitoh, Naonobu Fujita, Takuya Hayashi … (2009)
            Microbial nucleic acids are critical for the induction of innate immune responses, a host defense mechanism against infection by microbes. Recent studies have indicated that double-stranded DNA (dsDNA) induces potent innate immune responses via the induction of type I IFN (IFN) and IFN-inducible genes. However, the regulatory mechanisms underlying dsDNA-triggered signaling are not fully understood. Here we show that the translocation and assembly of the essential signal transducers, stimulator of IFN genes (STING) and TANK-binding kinase 1 (TBK1), are required for dsDNA-triggered innate immune responses. After sensing dsDNA, STING moves from the endoplasmic reticulum (ER) to the Golgi apparatus and finally reaches the cytoplasmic punctate structures to assemble with TBK1. The addition of an ER-retention signal to the C terminus of STING dampens its ability to induce antiviral responses. We also show that STING co-localizes with the autophagy proteins, microtubule-associated protein 1 light chain 3 (LC3) and autophagy-related gene 9a (Atg9a), after dsDNA stimulation. The loss of Atg9a, but not that of another autophagy-related gene (Atg7), greatly enhances the assembly of STING and TBK1 by dsDNA, leading to aberrant activation of the innate immune response. Hence Atg9a functions as a regulator of innate immunity following dsDNA stimulation as well as an essential autophagy protein. These results demonstrate that dynamic membrane traffic mediates the sequential translocation and assembly of STING, both of which are essential processes required for maximal activation of the innate immune response triggered by dsDNA.
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              Mechanism and function of deubiquitinating enzymes.

              Alexander Y. Amerik, Mark Hochstrasser (2004)
              Attachment of ubiquitin to proteins is a crucial step in many cellular regulatory mechanisms and contributes to numerous biological processes, including embryonic development, the cell cycle, growth control, and prevention of neurodegeneration. In these diverse regulatory settings, the most widespread mechanism of ubiquitin action is probably in the context of protein degradation. Polyubiquitin attachment targets many intracellular proteins for degradation by the proteasome, and (mono)ubiquitination is often required for down-regulating plasma membrane proteins by targeting them to the vacuole (lysosome). Ubiquitin-protein conjugates are highly dynamic structures. While an array of enzymes directs the conjugation of ubiquitin to substrates, there are also dozens of deubiquitinating enzymes (DUBs) that can reverse the process. Several lines of evidence indicate that DUBs are important regulators of the ubiquitin system. These enzymes are responsible for processing inactive ubiquitin precursors, proofreading ubiquitin-protein conjugates, removing ubiquitin from cellular adducts, and keeping the 26S proteasome free of inhibitory ubiquitin chains. The present review focuses on recent discoveries that have led to a better understanding the mechanisms and physiological roles of this diverse and still poorly understood group of enzymes. We also discuss briefly some of the proteases that act on ubiquitin-like protein (UBL) conjugates and compare them to DUBs.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Exp Med
                Journal ID (iso-abbrev): J. Exp. Med
                Journal ID (publisher-id): jem
                Journal ID (hwp): jem
                Title: The Journal of Experimental Medicine
                Publisher: The Rockefeller University Press
                ISSN (Print): 0022-1007
                ISSN (Electronic): 1540-9538
                Publication date (Print): 3 April 2017
                Volume: 214
                Issue: 4
                Pages: 991-1010
                Affiliations
                [1 ]Department of Central Laboratory, School of Life Science and Technology, Shanghai Tenth People’s Hospital of Tongji University, Tongji University, Shanghai 200072, China
                [2 ]Department of Clinical Laboratory Medicine, Shanghai Tenth People’s Hospital of Tongji University, Tongji University, Shanghai 200072, China
                [3 ]Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China
                [4 ]State Key Laboratory of Protein and Plant Gene Research, Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing 100000, China
                [5 ]Peking University-Tsinghua University Joint Center for Life Sciences, Beijing 100084, China
                [6 ]Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China
                Author notes
                Correspondence to Ping Wang: wangp@ 123456tongji.edu.cn
                [*]

                Y. Chen and L. Wang contributed equally to this paper.

                Author information
                http://orcid.org/0000-0003-0172-832X
                Article
                Publisher ID: 20161387
                DOI: 10.1084/jem.20161387
                PMC ID: 5379979
                PubMed ID: 28254948
                SO-VID: 0ecb8b9e-0302-4b17-9c32-4dd143b79ed4
                Copyright © © 2017 Chen et al.
                License:

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                Date received : 22 August 2016
                Date revision received : 05 November 2016
                Date accepted : 29 December 2016
                Funding
                Funded by: Ministry of Science and Technology of China, DOI https://doi.org/10.13039/501100002855;
                Award ID: 2012CB910404
                Funded by: National Natural Science Foundation of China, DOI https://doi.org/10.13039/501100001809;
                Award ID: 91519322
                Award ID: 91440104
                Award ID: 31501135
                Funded by: Ministry of Education of China, DOI https://doi.org/10.13039/501100002338;
                Award ID: 20130076110022
                Categories
                Subject: Research Articles
                Subject: Article
                Subject: 311
                Subject: 312

                ScienceOpen disciplines: Medicine
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                ScienceOpen disciplines: Medicine

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