Tripartite Motif 38 Attenuates Cardiac Fibrosis After Myocardial Infarction by Suppressing TAK1 Activation Via TAB2/3 Degradation

Overview

Journal iScience

Publisher Cell Press

Date 2022 Aug 19

PMID 35982795

Authors

Zhengri Lu

Chunshu Hao

Hao Qian

Yuanyuan Zhao

Xiangwei Bo

Yuyu Yao

Genshan Ma

Lijuan Chen

Affiliations

Soon will be listed here.

Abstract

The role of tripartite motif (TRIM) 38, a ubiquitin E3 ligase regulating various pathophysiological processes, in cardiac fibrosis remains unclear. Here, a model of angiotensin II and myocardial infarction (MI)-induced fibrosis was established to explore its role in cardiac fibrosis and its underlying mechanisms. Cardiac fibrosis in the mouse MI model was mitigated by TRIM38 overexpression, but aggravated by its depletion. Consistently, overexpression or knockdown of TRIM38 ameliorated or aggravated the proliferation and secretion of cardiac fibroblasts (CFs) exposed to fibrotic stimulation, respectively. Mechanistically, TRIM38 suppressed cardiac fibrosis progression by attenuating TAK1/MAPK signaling. Inhibiting TAK1/MAPK signaling with a pharmacological inhibitor greatly reversed the effects of TRIM38 knockdown on CF secretion. Specifically, TRIM38 interacted with and "targeted" TAB2 and TAB3 for degradation, subsequently inhibiting TAK1 phosphorylation and negatively regulating MAPK signaling. These findings can help develop therapeutic strategies to treat and prevent cardiac fibrosis.

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