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

• Published in: bioRxiv
• Main Authors: Fischer, Tara D, Bunker, Eric N, Zhu, Peng-Peng, Guerroué, François Le, Hadjian, Mahan, Dominguez-Martin, Eunice, Scavone, Francesco, Cohen, Robert, Yao, Tingting, Wang, Yan, Werner, Achim, Youle, Richard J
• Format: Journal Article
• Language: English
• Published: United States 01.10.2024
• Subjects: Golgi; Interferon; LC3B; LUBAC; Innate Immunity
• ISSN: 2692-8205; 2692-8205
• DOI: 10.1101/2023.10.14.562349

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.