Functional Skewing of TRIM21-SIRT5 Interplay Dictates IL-1β Production in DSS-induced colitis

Pengbo Yao # 1 2, Taiqi Chen # 2, Peng Jiang 2, Li Li 1, Wenjing Du 1

EMBO Rep.2022 Jun 30;e54391. doi: 10.15252/embr.202154391.

PMID: 35770730

Abstract

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)-1β 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-1β production during inflammation.