Professor Jin Jin’s group published a research paper on Journal of Clinical Investigation entitled “USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance” on May 28, 2019. This article revealed the mechanism of USP16 controls peripheral T cell activation and USP16 might serve as a novel therapeutic target in the treatment of T cell-mediated autoimmune diseases.
USP16 is a deubiquitinase that has been found to be required for chromosomal segregation in mitosis.Dysregulated expression of USP16 is associated with Down Syndrome, in addition to multiple organic developmental disorders, patients with Down syndrome have an increased risk of developing acute lymphoblastic leukemia celiac disease, however the mechanism remains unclear and the function of USP16 in autoimmune diseases needs to be investigated. In this study, we found that USP16 increased in peripheral CD4+ T cells collected from patients with different autoimmune diseases, but the mechanisms of T cells activated by USP16 remain poorly understood.
It shows that USP16 deficiency attenuates T cell-mediated autoimmune diseases, USP16TKO mice exhibited a significantly delayed onset of experimental autoimmune encephalomyelitis (EAE), demonstrated by the assessment of EAE clinical scoresand a substantially reduced level of central nervous system infiltration. The transfer of naïve CD45RBhi CD4+ T cells from USP16TKO mice into Rag1-/- mice did not induce body weight loss or inflammation-triggered death to the same extent as in WT controls or epithelial denudation.
HE staining of colon tissue
In this study, we found that USP16 deficiency leads to impaired peripheral T cell maintenance and USP16 is essential for T cell activation and proliferation. Moreover, USP16 participate TCR driven Calcineurin-NFAT axis signaling, it is selectively associated with CNA encoded by Ppp3cb and Ppp3cc and then specifically removes the K29-linked polyubiquitin chain of CNA. The deubiquitinated CNA activated NFAT and increased nuclear translocation of NFAT.
Taken together, this study identifies USP16 controls maintenance, proliferation and activation of peripheral T cells through regulating calcineurin-dependent NFAT activity, and a novel immunosuppressive drug target for the treatment of autoimmune diseases.
Graduate student Yu Zhang, Rongbei Liu, Keqi Fan, Prof. Qian Cao of Sir Run Run Shaw Hospital of Zhejiang University are co-first authors of this study. Prof. Jin is the corresponding author. This work was supported by grants from excellent young scientist fund and general Program of NFSC, Thousand Talents Plan and Distinguished Young Scholars of Zhejiang NSFC.
Links: https://www.jci.org/articles/view/123801
