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TRIM55 promotes noncanonical NF-kB signaling and B-cell-mediated immune responses by coordinating p100 ubiquitination and processing

ABSTRACT: The ubiquitination-dependent processing of NF-B2 (also known as p100) is a critical step in the activation of the noncanonical NF-B pathway. We investigated the molecular mechanisms regulating this process and showed that TRIM55 was the ubiquitin E3 ligase that mediated the ubiquitination of p100 and coordinated its processing. TRIM55 deficiency impaired noncanonical NF-B activation and B-cell function. Mice with a B cell-specific Trim55 deficiency exhibited reduced germinal center formation and antibody production. In addition, our data indicated a critical role of TRIM55 in the pathogenesis of lupus-like autoimmunological disorders, suggesting B-cell intrinsic functions of TRIM55 in humoral immune responses and autoimmunity. Mechanistically, the ubiquitination of p100 mediated by TRIM55 was crucial for p100 processing by VCP, an ATPase that mediates ubiquitin-dependent protein degradation by the proteasome. Furthermore, we found that TRIM55 facilitated the interaction between TRIM21 and VCP as well as TRIM21-mediated K63-ubiquitination of VCP, both of which were indispensable for the formation of the VCP-UFD1-NPL4 complex and p100 processing. Collectively, our results revealed a mechanism by which TRIM55 fine-tunes p100 processing and regulates B-cell-dependent immune responses in vivo, highlighting TRIM55 as a potential therapeutic target for lupus-like disease.

ORGANISM(S): Mus Musculus

SUBMITTER: Lunzhi Dai

PROVIDER: PXD044895 | iProX | Mon Aug 28 00:00:00 BST 2023

REPOSITORIES: iProX

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TRIM55 promotes noncanonical NF-κB signaling and B cell-mediated immune responses by coordinating p100 ubiquitination and processing.

Lin Liangbin L Yu Hui H Li Li L Yang Wenyong W Chen Xueying X Gong Yanqiu Y Lei Qingqiang Q Li Zhonghan Z Zhou Zhaocai Z Dai Lunzhi L Zhang Huiyuan H Hu Hongbo H

Science signaling 20231010 806

The ubiquitination-dependent processing of NF-κB2 (also known as p100) is a critical step in the activation of the noncanonical NF-κB pathway. We investigated the molecular mechanisms regulating this process and showed that TRIM55 was the E3 ubiquitin ligase that mediated the ubiquitination of p100 and coordinated its processing. TRIM55 deficiency impaired noncanonical NF-κB activation and B cell function. Mice with a B cell-specific <i>Trim55</i> deficiency exhibited reduced germinal center for ...[more]

PMID: 37816088

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Dataset Information

TRIM55 promotes noncanonical NF-kB signaling and B-cell-mediated immune responses by coordinating p100 ubiquitination and processing

Publications

TRIM55 promotes noncanonical NF-κB signaling and B cell-mediated immune responses by coordinating p100 ubiquitination and processing.

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