LTN1 promotes RLR degradation to inhibit immune response to RNA virus through the ESCRT pathway

• Published in: Autophagy Vol. 20; no. 6; pp. 1270 - 1285
• Main Authors: Qin, Fei, Cai, Baoshan, Wang, Peng, Cao, Runyu, Zhang, Yuling, Wen, Hongling, Zheng, Yi, Zhao, Wei, Gao, Chengjiang, Liu, Bingyu
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.06.2024
• Subjects: Animals; Antiviral innate immunity; DEAD Box Protein 58 - metabolism; Endosomal Sorting Complexes Required for Transport - metabolism; ESCRT; HEK293 Cells; Humans; Immunity, Innate; Interferon-Induced Helicase, IFIH1 - metabolism; LTN1; Mice; Proteolysis; RLR; RNA Viruses - immunology; RNA Viruses - physiology; Signal Transduction; Tripartite Motif Proteins - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; LTN1; RLR; ESCRT; ubiquitination; Antiviral innate immunity
• ISSN: 1554-8627; 1554-8635; 1554-8635
• DOI: 10.1080/15548627.2023.2291939

The excessive activation of immune responses will trigger autoimmune diseases or inflammatory injury. The endosomal sorting complexes required for transport (ESCRT) system can capture and mediate ubiquitinated protein degradation, which timely terminates signaling pathway hyperactivation. However, whether the ESCRT system participates in regulating RIGI-like receptor (RLR)-mediated antiviral responses remains unknown. In this study, we show that LTN1/listerin, a major component of RQC, can recruit E3 ubiquitin ligase TRIM27 to trigger K63-linked polyubiquitination of RIGI and IFIH1/MDA5. This K63-linked polyubiquitination facilitates the sorting and degradation of RIGI and IFIH1 proteins through the ESCRT-dependent pathway. Concordantly, LTN1 deficiency enhances the innate antiviral response to infection with RNA viruses. Thus, our work uncovers a new mechanism for RIGI and IFIH1 degradation and identifies the role of LTN1 in negatively regulating RLR-mediated antiviral innate immunity, which may provide new targets for the intervention of viral infection. Abbreviation: 5'-pppRNA: 5' triphosphate double stranded RNA; ATG5: autophagy related 5; ATG7: autophagy related 7; BafA1: bafilomycin A 1 ; ESCRT: endosomal sorting complexes required for transport; CHX: cycloheximide; IFIH1/MDA5: interferon induced with helicase C domain 1; IFN: interferon; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; RIGI: RNA sensor RIG-I; RLR: RIGI-like receptors; RQC: ribosome-associated protein quality control; SeV: Sendai virus; TRIM27: tripartite motif-containing 27; VSV: vesicular stomatitis virus; VPS4: vacuolar protein sorting 4.