STING induces HOIP-mediated synthesis of M1 ubiquitin chains to stimulate NFκB signaling.

Autor: Fischer TD; Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health; Bethesda, MD, USA., Bunker EN; Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health; Bethesda, MD, USA., Zhu PP; Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health; Bethesda, MD, USA., Guerroué FL; Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health; Bethesda, MD, USA., Hadjian M; Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health; Bethesda, MD, USA., Dominguez-Martin E; Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health; Bethesda, MD, USA., Scavone F; Department of Biochemistry and Molecular Biology, Colorado State University; Fort Collins, CO, USA., Cohen R; Department of Biochemistry and Molecular Biology, Colorado State University; Fort Collins, CO, USA., Yao T; Department of Biochemistry and Molecular Biology, Colorado State University; Fort Collins, CO, USA., Wang Y; Mass Spectrometry, National Institute of Dental and Craniofacial Research, National Institutes of Health; Bethesda, MD, USA., Werner A; Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health; Bethesda, MD, USA., Youle RJ; Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health; Bethesda, MD, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 01. Date of Electronic Publication: 2024 Oct 01.
DOI: 10.1101/2023.10.14.562349
Abstrakt: STING activation by cyclic dinucleotides in mammals induces IRF3- and NFκB -mediated gene expression, and the lipidation of LC3B at Golgi-related membranes. While mechanisms of the IRF3 response are well understood, the mechanisms of NFκB activation mediated by STING remain unclear. We report that STING activation induces linear/M1-linked ubiquitin chain (M1-Ub) formation and recruitment of the LUBAC E3 ligase, HOIP, to LC3B-associated Golgi membranes where ubiquitin is also localized. Loss of HOIP prevents formation of M1-Ub ubiquitin chains and reduces STING-induced NFκB and IRF3-mediated signaling in human monocytic THP1 cells and mouse bone marrow derived macrophages, without affecting STING activation. STING-induced LC3B lipidation is not required for M1-Ub chain formation or the immune-related gene expression, however the recently reported function of STING to neutralize the pH of the Golgi may be involved. Thus, LUBAC synthesis of M1 ubiquitin chains mediates STING-induced innate immune signaling.
Databáze: MEDLINE