SEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway

作者：Beibei Fu, Yan Xiong, Zhou Sha, Weiwei Xue, Binbin Xu, Shun Tan, Dong Guo, Feng Lin, Lulu Wang, Jianjian Ji, Yang Luo, Xiaoyuan Lin, Haibo Wu · 发表于：Nature Communications · 年份：2023 · DOI：10.1038/s41467-023-43283-2 · 被引用次数：56 · 研究领域：Immune cells in cancer、Autophagy in Disease and Therapy、Endoplasmic Reticulum Stress and Disease

Interferon-gamma (IFN-γ) signaling is necessary for the proinflammatory activation of macrophages but IFN-γ-independent pathways, for which the initiating stimuli and downstream mechanisms are lesser known, also contribute. Here we identify, by high-content screening, SEPTIN2 (SEPT2) as a negative regulation of IFN-γ-independent macrophage autoactivation. Mechanistically, endoplasmic reticulum (ER) stress induces the expression of SEPT2, which balances the competition between acetylation and ubiquitination of heat shock protein 5 at position Lysine 327, thereby alleviating ER stress and constraining M1-like polarization and proinflammatory cytokine release. Disruption of this negative feedback regulation leads to the accumulation of unfolded proteins, resulting in accelerated M1-like polarization, excessive inflammation and tissue damage. Our study thus uncovers an IFN-γ-independent macrophage proinflammatory autoactivation pathway and suggests that SEPT2 may play a role in the prevention or resolution of inflammation during infection.