The Role Of USP16 In Exacerbating Intestinal Inflammation By Mediating Deubiquitination Of Calcineurin A

Inflammatory bowel disease(IBD)is an autoimmune disease characterized by chronic intestinal non-specific inflammation,including ulcerative colitis(UC)and Crohn's Disease(CD).IBD leads to poor quality of life of patients and significant economic burden on the health care system.The pathogenesis of IBD is unclear yet,it may be associated with genetic factors,environmental factors and immunity,it is believed that abnormal activation and dysfunction of T cells play an important role in the development of IBD.We analyzed data from public database and found that the increasement of ubiquitin carboxyl-terminal hydrolase 16(USP16)in peripheral CD4+T cells in patients with different autoimmune diseases.However,the underlying mechanism by which USP16 mediates T cell overactivation is still unclear.Therefore,we aimed to explore the mechanism by which USP16 involved in the pathogenesis of IBD by mediating T cell function.To clarified this situation,we collected peripheral blood mononuclear cells(PBMCs)and CD4+T cells from IBD patients for detection of Usp16 expression,the results showed that the expression of Usp16 in the PBMCs and CD4+T cells of IBD patients was significantly higher than that of normal people.To further investigate the involvement of USP16 in the pathophysiology and regulation of IBD,we constructed a conditional-knockout-mice with Usp16 knockout in T cells(Usp16TKO).The T cells transfer colitis model were constructed,and we found that Rag1-/-mice received from Usp16TKO mice showed milder intestinal inflammation and a more complete intestinal barrier than that from WT mice.Then,we found that USP16 is essential for activation,proliferation and differentiation of T cells.Then we screened the T cell signaling pathway(TCR)protein,the results showed that USP16 promote NFAT nuclear translocation and specifically binding to its upstream protein calcineurin.The K29-linked ubiquitination of CNA impaired NFAT recruitment and the transcription of NFAT-targeted genes.Our work elucidates the physiological function of calcineurin ubiquitination and its deubiquitinase USP16 in peripheral T cells.Notably,our results provide a critical mechanism for the regulation of calcineurin activity and a novel immunosuppressive drug target for the treatment of autoimmune diseases.