Dataset Information

TRIM26 positively regulates the inflammatory immune response through K11-linked ubiquitination of TAB1.

ABSTRACT: Protein ubiquitination plays an important role in the regulation of TGF-β-activated kinase 1 (TAK1)-mediated NF-κB activation. It is well established that TAK1 activation is tightly regulated with its binding partners, TAK1-binding proteins (TAB1-3). However, the tight regulation of TAK1 activation remains elusive. Here, using Trim26-knockout mice and Trim26-transgenic mice, we found that TRIM26 acts as a positive regulator of TAK1 activation by ubiquitinating its binding partner TAB1. Knockout of Trim26 inhibited TAK1 activation and downstream kinases activation, thus decreasing the induction of proinflammatory cytokines following LPS, TNF-α, and IL-1β stimulation. Mechanistically, TRIM26 catalyzes the K11-linked polyubiquitination of TAB1 at Lys294, Lys319, and Lys335 to enhance the activation of TAK1 and subsequent NF-κB and MAPK signaling. Consequently, Trim26 deficiency protects mice from LPS-induced septic shock in vivo. Moreover, Trim26 deficiency attenuates the severity of dextran sodium sulfate (DSS)-induced colitis. Thus, these finding provides a novel insight into how TAK1 activation is regulated through TRIM26-mediated ubiquitination of TAB1 and reveals the new function of TRIM26 in the regulation of the inflammatory innate immune response.

SUBMITTER: Zhao J

PROVIDER: S-EPMC8563735 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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TRIM26 positively regulates the inflammatory immune response through K11-linked ubiquitination of TAB1.

Zhao Jian J Cai Baoshan B Shao Zhugui Z Zhang Lei L Zheng Yi Y Ma Chunhong C Yi Fan F Liu Bingyu B Gao Chengjiang C

Cell death and differentiation 20210520 11

Protein ubiquitination plays an important role in the regulation of TGF-β-activated kinase 1 (TAK1)-mediated NF-κB activation. It is well established that TAK1 activation is tightly regulated with its binding partners, TAK1-binding proteins (TAB1-3). However, the tight regulation of TAK1 activation remains elusive. Here, using Trim26-knockout mice and Trim26-transgenic mice, we found that TRIM26 acts as a positive regulator of TAK1 activation by ubiquitinating its binding partner TAB1. Knockout ...[more]

PMID: 34017102

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Project description:RationaleCompromised protein quality control can result in proteotoxic intracellular protein aggregates in the heart, leading to cardiac disease and heart failure. Defining the participants and understanding the underlying mechanisms of cardiac protein aggregation is critical for seeking therapeutic targets. We identified Ube2v1 (ubiquitin-conjugating enzyme E2 variant 1) in a genome-wide screen designed to identify novel effectors of the aggregation process. However, its role in the cardiomyocyte is undefined.ObjectiveTo assess whether Ube2v1 regulates the protein aggregation caused by cardiomyocyte expression of a mutant αB crystallin (CryABR120G) and identify how Ube2v1 exerts its effect.Methods and resultsNeonatal rat ventricular cardiomyocytes were infected with adenoviruses expressing either wild-type CryAB (CryABWT) or CryABR120G. Subsequently, loss- and gain-of-function experiments were performed. Ube2v1 knockdown decreased aggregate accumulation caused by CryABR120G expression. Overexpressing Ube2v1 promoted aggregate formation in CryABWT and CryABR120G-expressing neonatal rat ventricular cardiomyocytes. Ubiquitin proteasome system performance was analyzed using a ubiquitin proteasome system reporter protein. Ube2v1 knockdown improved ubiquitin proteasome system performance and promoted the degradation of insoluble ubiquitinated proteins in CryABR120G cardiomyocytes but did not alter autophagic flux. Lys (K) 63-linked ubiquitination modulated by Ube2v1 expression enhanced protein aggregation and contributed to Ube2v1's function in regulating protein aggregate formation. Knocking out Ube2v1 exclusively in cardiomyocytes by using AAV9 (adeno-associated virus 9) to deliver multiplexed single guide RNAs against Ube2v1 in cardiac-specific Cas9 mice alleviated CryABR120G-induced protein aggregation, improved cardiac function, and prolonged lifespan in vivo.ConclusionsUbe2v1 plays an important role in protein aggregate formation, partially by enhancing K63 ubiquitination during a proteotoxic stimulus. Inhibition of Ube2v1 decreases CryABR120G-induced aggregate formation through enhanced ubiquitin proteasome system performance rather than autophagy and may provide a novel therapeutic target to treat cardiac proteinopathies.

Dataset Information

TRIM26 positively regulates the inflammatory immune response through K11-linked ubiquitination of TAB1.

Publications

TRIM26 positively regulates the inflammatory immune response through K11-linked ubiquitination of TAB1.

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