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
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health; Bethesda, MD, USA.
Department of Biochemistry and Molecular Biology, Colorado State University; Fort Collins, CO, USA.
bioRxiv. 2024 Oct 1:2023.10.14.562349. 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.
在哺乳动物中，环状二核苷酸激活STING可诱导IRF3和NFκB介导的基因表达，以及高尔基体相关膜上LC3B的脂化。虽然IRF3应答的机制已得到充分了解，但STING介导的NFκB激活机制仍不清楚。我们报告称，STING激活可诱导线性/M1连接的泛素链（M1-Ub）形成，并将LUBAC E3连接酶HOIP招募到泛素也定位的与LC3B相关的高尔基体膜上。HOIP缺失可阻止M1-Ub泛素链的形成，并减少人单核细胞THP1细胞和小鼠骨髓来源巨噬细胞中STING诱导的NFκB和IRF3介导的信号传导，而不影响STING激活。M1-Ub链形成或免疫相关基因表达不需要STING诱导的LC3B脂化，然而，最近报道的STING中和高尔基体pH值的功能可能与之有关。因此，M1泛素链的LUBAC合成介导了STING诱导的先天免疫信号传导。
