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  1. Article ; Online: K63-linked polyubiquitination of LGP2 by Riplet regulates RIG-I-dependent innate immune response.

    Kouwaki, Takahisa / Nishimura, Tasuku / Wang, Guanming / Nakagawa, Reiko / Oshiumi, Hiroyuki

    EMBO reports

    2022  Volume 24, Issue 2, Page(s) e54844

    Abstract: Type I interferons (IFNs) exhibit strong antiviral activity and induce the expression of antiviral proteins. Since excessive expression of type I IFNs is harmful to the host, their expression should be turned off at the appropriate time. In this study, ... ...

    Abstract Type I interferons (IFNs) exhibit strong antiviral activity and induce the expression of antiviral proteins. Since excessive expression of type I IFNs is harmful to the host, their expression should be turned off at the appropriate time. In this study, we find that post-translational modification of LGP2, a member of the RIG-I-like receptor family, modulates antiviral innate immune responses. The LGP2 protein undergoes K63-linked polyubiquitination in response to cytoplasmic double-stranded RNAs or viral infection. Our mass spectrometry analysis reveals the K residues ubiquitinated by the Riplet ubiquitin ligase. LGP2 ubiquitination occurs with a delay compared to RIG-I ubiquitination. Interestingly, ubiquitination-defective LGP2 mutations increase the expression of type I IFN at a late phase, whereas the mutant proteins attenuate other antiviral proteins, such as SP100, PML, and ANKRD1. Our data indicate that delayed polyubiquitination of LGP2 fine-tunes RIG-I-dependent antiviral innate immune responses at a late phase of viral infection.
    MeSH term(s) Humans ; Antiviral Agents ; DEAD Box Protein 58/genetics ; DEAD Box Protein 58/metabolism ; DEAD-box RNA Helicases/genetics ; Immunity, Innate ; Interferon Type I/genetics ; Ubiquitin/metabolism ; Ubiquitination ; Virus Diseases
    Chemical Substances Antiviral Agents ; DEAD Box Protein 58 (EC 3.6.4.13) ; DEAD-box RNA Helicases (EC 3.6.4.13) ; Interferon Type I ; Ubiquitin ; RIGI protein, human (EC 3.6.1.-) ; DHX58 protein, human (EC 2.7.7.-)
    Language English
    Publishing date 2022-12-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2020896-0
    ISSN 1469-3178 ; 1469-221X
    ISSN (online) 1469-3178
    ISSN 1469-221X
    DOI 10.15252/embr.202254844
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: RIG-I-Like Receptor-Mediated Recognition of Viral Genomic RNA of Severe Acute Respiratory Syndrome Coronavirus-2 and Viral Escape From the Host Innate Immune Responses.

    Kouwaki, Takahisa / Nishimura, Tasuku / Wang, Guanming / Oshiumi, Hiroyuki

    Frontiers in immunology

    2021  Volume 12, Page(s) 700926

    Abstract: RIG-I-like receptors (RLR), RIG-I and MDA5, are cytoplasmic viral RNA sensors that recognize viral double-stranded RNAs and trigger signals to induce antiviral responses, including type I interferon production. Severe acute respiratory syndrome ... ...

    Abstract RIG-I-like receptors (RLR), RIG-I and MDA5, are cytoplasmic viral RNA sensors that recognize viral double-stranded RNAs and trigger signals to induce antiviral responses, including type I interferon production. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused the coronavirus disease 2019 pandemic. However, the RLR role in innate immune response to SARS-CoV-2 has not been fully elucidated. Here, we studied the roles of RLR in cytokine expression responding to SARS-CoV-2 and found that not only MDA5 but also RIG-I are involved in innate immune responses in some types of human cells. Transfection of total RNAs extracted from SARS-CoV-2-infected cells into epithelial cells induced IFN-β, IP-10, and Ccl5 mRNA expression. The cytokine expression was reduced by knockout of either RIG-I or MDA5, suggesting that both proteins are required for appropriate innate immune response to SARS-CoV-2. Two viral genomic RNA regions strongly induced type I IFN expression, and a 200-base fragment of viral RNA preferentially induced type I IFN in a RIG-I-dependent manner. In contrast, SARS-CoV-2 infectious particles hardly induced cytokine expression, suggesting viral escape from the host response. Viral 9b protein inhibited RIG-I and MAVS interaction, and viral 7a protein destabilized the TBK1 protein, leading to attenuated IRF-3 phosphorylation required for type I IFN expression. Our data elucidated the mechanism underlying RLR-mediated response to SARS-CoV-2 infection and viral escape from the host innate immune response.
    MeSH term(s) COVID-19/immunology ; Gene Knockdown Techniques ; HEK293 Cells ; Host-Pathogen Interactions ; Humans ; Immune Evasion ; Immunity, Innate ; Interferon Regulatory Factor-3/metabolism ; Interferon Type I/metabolism ; Interferon-Induced Helicase, IFIH1/genetics ; Interferon-Induced Helicase, IFIH1/metabolism ; Phosphorylation ; RNA, Viral/immunology ; Receptors, Retinoic Acid/genetics ; Receptors, Retinoic Acid/metabolism ; SARS-CoV-2/physiology ; Severe Acute Respiratory Syndrome/immunology ; Signal Transduction ; Viral Matrix Proteins/metabolism
    Chemical Substances IRF3 protein, human ; Interferon Regulatory Factor-3 ; Interferon Type I ; PLAAT4 protein, human ; RNA, Viral ; Receptors, Retinoic Acid ; Viral Matrix Proteins ; sars7a protein, SARS virus ; IFIH1 protein, human (EC 3.6.1.-) ; Interferon-Induced Helicase, IFIH1 (EC 3.6.4.13)
    Language English
    Publishing date 2021-06-25
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2021.700926
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Ubiquitin ligase RIPLET mediates polyubiquitination of RIG-I and LGP2 and regulates the innate immune responses to SARS-CoV-2 infection

    Kouwaki, Takahisa / Nishimura, Tasuku / Wang, Guanming / Nakagawa, Reiko / Oshiumi, Hiroyuki

    bioRxiv

    Abstract: RIG-I, a cytoplasmic viral RNA sensor, is crucial for innate antiviral immune responses; however, there are controversies about the regulatory mechanism of RIG-I by several ubiquitin ligases and LGP2. This study revealed that the RIPLET ubiquitin ligase ... ...

    Abstract RIG-I, a cytoplasmic viral RNA sensor, is crucial for innate antiviral immune responses; however, there are controversies about the regulatory mechanism of RIG-I by several ubiquitin ligases and LGP2. This study revealed that the RIPLET ubiquitin ligase is a general activating factor for RIG-I signaling. In contrast, another ubiquitin ligase, TRIM25, activated RIG-I in a cell-type-specific manner. RIPLET and TRIM25 functions were modulated by accessory factors, such as ZCCH3C and NLRP12. Interestingly, we found an additional role of RIPLET in innate immune responses. RIPLET induced delayed polyubiquitination of LGP, resulting in the attenuation of excessive cytokine expression at the late phase. Moreover, RIPLET was involved in the innate immune responses against SARS-CoV-2 infection, a cause of the recent COVID-19 pandemic. Our data indicate that RIPLET fine-tunes innate immune responses via polyubiquitination of RIG-I and LGP2 against virus infection, including SARS-CoV-2.
    Keywords covid19
    Language English
    Publishing date 2021-01-25
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2021.01.25.428042
    Database COVID19

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  4. Article ; Online: Riplet Ubiquitin Ligase Regulates Innate Antiviral Immune Responses Via Lysine 63-Linked Polyubiquitination of RIG-I and LGP2 and is Essential for Protection Against SARS-CoV-2

    Kouwaki, Takahisa / Nishimura, Tasuku / Wang, Guanming / Nakagawa, Reiko / Oshiumi, Hiroyuki

    SSRN Electronic Journal ; ISSN 1556-5068

    2020  

    Keywords covid19
    Language English
    Publisher Elsevier BV
    Publishing country us
    Document type Article ; Online
    DOI 10.2139/ssrn.3677228
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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