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

Author

Listed:
  • Beibei Fu

    (Chongqing University)

  • Yan Xiong

    (Chongqing University)

  • Zhou Sha

    (Chongqing University)

  • Weiwei Xue

    (Chongqing University)

  • Binbin Xu

    (Chongqing University)

  • Shun Tan

    (Chongqing Public Health Medical Center)

  • Dong Guo

    (Chongqing University)

  • Feng Lin

    (Chongqing University)

  • Lulu Wang

    (Chongqing University)

  • Jianjian Ji

    (Nanjing University of Chinese Medicine)

  • Yang Luo

    (Chongqing University)

  • Xiaoyuan Lin

    (Freie Universität Berlin
    Army Medical University (Third Military Medical University))

  • Haibo Wu

    (Chongqing University
    Chongqing University)

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.

Suggested Citation

  • 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, 2023. "SEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43283-2
    DOI: 10.1038/s41467-023-43283-2
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    1. Pamela P. Lee & Damián Lobato-Márquez & Nayani Pramanik & Andrea Sirianni & Vanessa Daza-Cajigal & Elizabeth Rivers & Alessia Cavazza & Gerben Bouma & Dale Moulding & Kjell Hultenby & Lisa S. Westerbe, 2017. "Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
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