title: Linear ubiquitin assembly complex negatively regulates RIG-I- and TRIM25-mediated type I interferon induction.
abstract: Upon detection of viral RNA, retinoic acid-inducible gene I (RIG-I) undergoes TRIM25-mediated K63-linked ubiquitination, leading to type I interferon (IFN) production. In this study, we demonstrate that the linear ubiquitin assembly complex (LUBAC), comprised of two RING-IBR-RING (RBR)-containing E3 ligases, HOIL-1L and HOIP, independently targets TRIM25 and RIG-I to effectively suppress virus-induced IFN production. RBR E3 ligase domains of HOIL-1L and HOIP bind and induce proteasomal degradation of TRIM25, whereas the NZF domain of HOIL-1L competes with TRIM25 for RIG-I binding. Consequently, both actions by the HOIL-1L/HOIP LUBAC potently inhibit RIG-I ubiquitination and antiviral activity, but in a mechanistically separate manner. Conversely, the genetic deletion or depletion of HOIL-1L and HOIP robustly enhances virus-induced type I IFN production. Taken together, the HOIL-1L/HOIP LUBAC specifically suppresses RIG-I ubiquitination and activation by inducing TRIM25 degradation and inhibiting TRIM25 interaction with RIG-I, resulting in the comprehensive suppression of the IFN-mediated antiviral signaling pathway.
authors.affiliation: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Inn
authors.forename: Michaela U
authors.initials: MU
authors.lastname: Gack
authors.forename: Fuminori
authors.initials: F
authors.lastname: Tokunaga
authors.forename: Mude
authors.initials: M
authors.lastname: Shi
authors.forename: Lai-Yee
authors.initials: LY
authors.lastname: Wong
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D007370:Interferon Type I; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; C437968:PLAAT4 protein, human; C084523:TRIM25 protein, human; C000607389:Rbck1 protein, mouse