E3 ubiquitin ligase STUB1 affects the mTORC1 pathway through p62 and participates in regulating the differentiation of follicular helper T cells in rheumatoid arthritis

Abstract

Objective: The abnormal expansion of Tfh cells plays a key role in chronic inflammation of RA joint. We speculated that STUB1 is an important regulatory factor in promoting the differentiation of Tfh cells in RA.

Content and methods: The proportion of Tfh cells and the level of STUB1 in Tfh cells was measured. CD4⁺T cells were isolated from PBMCs of RA patients, and the percentage of Tfh cells was detected after up- or down-regulating the expression of STUB1. The levels of mTORC1 pathway activator p-mTOR and p-S6K were measured by Western blot. The ubiquitination of p62 by STUB1 and its ubiquitination type as well as the activation of mTORC1 was detected in vitro, and the activation of the mTORC1 and the differentiation of Tfh cells was detected in STUB1-upregulated CD4⁺ T cells with overexpressed p62.

Results: The level of STUB1 is elevated in Tfh cells of patients. Up-regulation of STUB1 can promote the differentiation of Tfh cells. STUB1 promotes the degradation of p62 via K48-linked ubiquitination and promotes the activation of mTORC1. Overexpression of p62 can reverse the promoting effect of STUB1 on the differentiation of Tfh cells and the activation of mTORC1.

Conclusion: STUB1 can promote the differentiation of Tfh cells in RA by mediating the activation of mTORC1 pathway through ubiquitination of p62.

Keywords: E3 ubiquitin ligases STUB1; Follicular helper T cells; Rheumatoid arthritis; mTORC1 pathway; p62.