2. Academic Validation
  3. SEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway

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

  • Nat Commun. 2023 Nov 17;14(1):7441. doi: 10.1038/s41467-023-43283-2.
Beibei Fu # 1,  Yan Xiong # 1,  Zhou Sha 1,  Weiwei Xue 2,  Binbin Xu 2,  Shun Tan 3,  Dong Guo 1,  Feng Lin 1,  Lulu Wang 1,  Jianjian Ji 4,  Yang Luo 5,  Xiaoyuan Lin 6 7,  Haibo Wu 8 9
Affiliations

Affiliations

  • 1 School of Life Sciences, Chongqing University, 401331, Chongqing, China.
  • 2 School of Pharmaceutical Sciences, Chongqing University, 401331, Chongqing, China.
  • 3 Chongqing Public Health Medical Center, 400036, Chongqing, China.
  • 4 Jiangsu Key Laboratory of Pediatric Respiratory Disease, Institute of Pediatrics, Nanjing University of Chinese Medicine, 210023, Nanjing, China.
  • 5 Center of Smart Laboratory and Molecular Medicine, School of Medicine, NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing University, 400044, Chongqing, China. [email protected].
  • 6 Institut für Virologie, Freie Universität Berlin, Robert-von-Ostertag-Str. 7-13, 14163, Berlin, Germany. [email protected].
  • 7 Department of Clinical Microbiology and Immunology, College of Pharmacy and Medical Laboratory, Army Medical University (Third Military Medical University), 400038, Chongqing, China. [email protected].
  • 8 School of Life Sciences, Chongqing University, 401331, Chongqing, China. [email protected].
  • 9 Center of Smart Laboratory and Molecular Medicine, School of Medicine, NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing University, 400044, Chongqing, China. [email protected].
  • # Contributed equally.
PMID: 37978190 DOI: 10.1038/s41467-023-43283-2
Abstract

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.

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