| First Author | Fu B | Year | 2023 |
| Journal | Nat Commun | Volume | 14 |
| Issue | 1 | Pages | 7441 |
| PubMed ID | 37978190 | Mgi Jnum | J:358240 |
| Mgi Id | MGI:7560898 | Doi | 10.1038/s41467-023-43283-2 |
| Citation | Fu B, et al. (2023) SEPTIN2 suppresses an IFN-gamma-independent, proinflammatory macrophage activation pathway. Nat Commun 14(1):7441 |
| abstractText | Interferon-gamma (IFN-gamma) signaling is necessary for the proinflammatory activation of macrophages but IFN-gamma-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-gamma-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-gamma-independent macrophage proinflammatory autoactivation pathway and suggests that SEPT2 may play a role in the prevention or resolution of inflammation during infection. |
