Functional skewing of TRIM21-SIRT5 interplay dictates IL-1β production in DSS-induced colitis
Functional skewing of TRIM21-SIRT5 interplay dictates IL-1β production in DSS-induced colitis
复制标题
TRIM21-SIRT5 相互作用的功能偏斜决定 DSS 诱导的结肠炎中 IL-1β 的产生
DOI：
10.15252/embr.202154391
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发表时间：
2022
期刊：
影响因子：
7.7
通讯作者：
Wenjing Du
中科院分区：
文献类型：
--
作者：
Pengbo Yao;Taiqi Chen;Peng Jiang;Li Li;Wenjing Du
巨噬细胞极化决定了对各种细菌和病毒感染的促炎性或抗炎性细胞因子的产生。在这里，我们报道了脂多糖（LPS）诱导的促炎巨噬细胞极化使TRIM21-SIRT5的相互作用偏向TRIM21激活和SIRT5降解，导致体外和体内白细胞介素(IL)-1β的产生增强。在机制上，LPS刺激增强TRIM21和SIRT5之间的相互作用，促进SIRT5的泛素化和降解，同时减少SIRT5与HAUSP的结合，HAUSP是一种稳定SIRT5的去泛素化酶。在一个反馈回路中，SIRT5降解维持TRIM21在Lys351位点的乙酰化，从而增加其在lps活化的巨噬细胞中的E3连接酶活性。因此，我们确定了TRIM21和SIRT5之间的功能平衡，该平衡倾向于在LPS刺激下抑制SIRT5，从而增强炎症期间IL-1β的产生。
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.