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Ring finger protein 31-mediated atypical ubiquitination stabilizes forkhead box P3 and thereby stimulates regulatory T-cell function
Date:2019-07-17

FOXP3+ regulatory (Treg) cells are a specific subset of CD4+ T cells that are crucial for the maintenance of self-tolerance and immune homeostasis. The X-chromosome encoded transcription factor FOXP3 is essential for both Treg cell development and function. Treg cells become instable to acquire effector T cell function by losing FOXP3 expression, conversely, effector T cells manipulated to ectopically express FOXP3 gain the Treg cell phenotype. Though several studies, we have reported mechanisms related to FOXP3 protein stability in terms of post-translational modification, it still requires further exploration as to identifying novel binding partners that influence FOXP3 protein stability and Treg cell function. What is more, the complex network lying in Treg-inflammation requires more extensive studies.

In our study, we found that the E3 ubiquitin ligase RNF31 could potently upregulate FOXP3 expression by promoting its stability at the post-translational level through multi-mono-ubiquitination, which counters the degradation of FOXP3 triggering by inflammatory signals like LPS. Knock-down of RNF31 led to decreased FOXP3 protein and acquired a Th1-like phenotype in human Treg cells. In contrast, RNF31 ectopically expressing Treg cells displayed stronger suppressive capacity. TCR signaling pathway is positively associated with FOXP3 expression, we found that TCR signal also enhanced RNF31 level and FOXP3 ubiquitination, accompanied with FOXP3 protein upregulation. Interestingly, RNF31 was upregulated in human gastric tumor infiltrated Treg cells, compared with their peripheral and normal tissue resident counterparts. Elevated RNF31 expression in intra-tumor Treg cells was associated with poor survival of gastric cancer patients, thus providing a therapeutic target for the intervention against human gastric cancer. 

 

By Fuxiang Zhu

                 

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