A novel selective autophagy receptor, CCDC50, delivers K63 polyubiquitination-activated RIG-I/MDA5 for degradation during viral infection
Autor: | Penghui Jia, Deyin Guo, Kongxiang Yang, Weijie Zeng, Yuxin Lin, Zibo Li, Jun Li, Shuliang Chen, Junyu Wu, Yingfang Liu, Hong Peng, Lan Liu, Shuting Guo, Ji’An A. Pan, Chunmei Li, Panpan Hou |
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Rok vydání: | 2020 |
Předmět: |
Interferon-Induced Helicase
IFIH1 Biology Article Cell Line 03 medical and health sciences Mice 0302 clinical medicine Interferon Lysosome medicine Animals Humans RNA Viruses RNA Small Interfering Receptors Immunologic Receptor Molecular Biology 030304 developmental biology Mice Knockout 0303 health sciences Innate immune system Binding Sites RIG-I Autophagy Intracellular Signaling Peptides and Proteins NF-kappa B Ubiquitination MDA5 Cell Biology Cell biology medicine.anatomical_structure Interferon Type I DEAD Box Protein 58 RNA Interference Signal transduction Microtubule-Associated Proteins 030217 neurology & neurosurgery medicine.drug Signal Transduction |
Zdroj: | Cell Res |
ISSN: | 1748-7838 |
Popis: | Autophagy is a conserved process that delivers cytosolic substances to the lysosome for degradation, but its direct role in the regulation of antiviral innate immunity remains poorly understood. Here, through high-throughput screening, we discovered that CCDC50 functions as a previously unknown autophagy receptor that negatively regulates the type I interferon (IFN) signaling pathway initiated by RIG-I-like receptors (RLRs), the sensors for RNA viruses. The expression of CCDC50 is enhanced by viral infection, and CCDC50 specifically recognizes K63-polyubiquitinated RLRs, thus delivering the activated RIG-I/MDA5 for autophagic degradation. The association of CCDC50 with phagophore membrane protein LC3 is confirmed by crystal structure analysis. In contrast to other known autophagic cargo receptors that associate with either the LIR-docking site (LDS) or the UIM-docking site (UDS) of LC3, CCDC50 can bind to both LDS and UDS, representing a new type of cargo receptor. In mouse models with RNA virus infection, CCDC50 deficiency reduces the autophagic degradation of RIG-I/MDA5 and promotes type I IFN responses, resulting in enhanced viral resistance and improved survival rates. These results reveal a new link between autophagy and antiviral innate immune responses and provide additional insights into the regulatory mechanisms of RLR-mediated antiviral signaling. |
Databáze: | OpenAIRE |
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