Functional skewing of TRIM21-SIRT5 interplay dictates IL-1? production in DSS-induced colitis.

Macrophage polarization determines the production of pro- or anti-inflammatory cytokines in response to various bacterial and virus infections. Here, we report that pro-inflammatory macrophage polarization induced by lipopolysaccharide (LPS) skews the TRIM21-SIRT5 interplay toward TRIM21 activation and SIRT5 degradation, resulting in an enhancement of interleukin (IL)-1? production in?vitro and in?vivo. ...
Mechanistically, LPS challenge enhances the interaction between TRIM21 and SIRT5 to promote SIRT5 ubiquitination and degradation, while reducing the binding of SIRT5 to HAUSP, a deubiquitinating enzyme that stabilizes SIRT5. In a feedback loop, SIRT5 degradation sustains the acetylation of TRIM21 at Lys351, thereby increasing its E3 ligase activity in LPS-activated macrophages. Thus, we identify a functional balance between TRIM21 and SIRT5 that is tilted toward SIRT5 suppression in response to LPS stimulation, thereby enhancing IL-1? production during inflammation.
Mesh Terms:
Animals, Colitis, Cytokines, Interleukin-1beta, Lipopolysaccharides, Macrophages, Ribonucleoproteins, Sirtuins, Ubiquitination
EMBO Rep
Date: Dec. 05, 2021
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