Deubiquitinase BRCC3 ameliorates acute graft-versus-host disease and promotes graft-versus leukemia effects via promoting type I-IFN secretion

Abstract

Abstract Acute graft-versus-host disease (aGVHD) remains the leading cause of transplant related deaths after allogeneic hematopoietic stem cell transplantation (allo-HSCT). aGVHD is mediated by the activation of donor lymphocytes in response to the host antigens, and involves a variety of immune cells, inflammatory cytokines and multiple other cytokines. Previous studies have shown that type I-IFN plays an important role in balancing aGVHD and graft-versus leukemia (GVL) responses. Ubiquitination plays essential roles in the production of type I-IFN, but deubiqutinases (DUBs) were reported rarely. Here, we showed that BRCC3 overexpression enhanced IFNβ-luciferase activity, and knockdown of BRCC3 decreased the expression of IFNβ. Interestingly, BRCC3 was down-regulated in allo-HSCT mice compared to syngeneic HSCT (syn-HSCT) mice. We further found that overexpression of BRCC3 ameliorated aGVHD, while promoting GVL effects. Relevant mechanistic studies exhibited that BRCC3 promoted IFNβ production in aGVHD mice, and reduced the absolute numbers of CD4+ T cells and CD8+ T cells in aGVHD target organs. Furthermore, we found that BRCC3 physically interacts with the E3 ligase Trim25, which is involved in RIG-I signaling pathway. In addition, BRCC3 de-ubiquitinates and up-regulates Trim25. These findings suggest that BRCC3-mediated type I-IFN production may be a strategy to control aGVHD and promotes GVL responses.