The OTUD1-Notch2-ICD Axis Orchestrates Allogeneic T Cell-Mediated Graft-Versus-Host Disease

Abstract

Disorders of the ubiquitin-proteasome system (UPS) are known to influence the incidence and mortality of various diseases. It remains largely unknown whether and how the UPS affects the onset and progression of acute graft-versus host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The present study demonstrated that deubiquitinase OTUD1 is an essential regulator of aGVHD. OTUD1 expression level predicts the cumulative incidence and severity of aGVHD patients after allo-HSCT. Donor OTUD1 deficiency markedly prolonged the survival of aGVHD mice, reduced aGVHD scores, ameliorated pathological damage of target organs through inhibiting the differentiation and functions of Th1 and Th17 cells. Activation of CD4+ T cells after allo-HSCT elevated the expression of OTUD1, which in turn interacted with the Notch2-ICD (NICD) protein to cleave the ubiquitin of NICD at the K1770 site, thereby inducing the accumulation of the NICD proteins in T cells. OTUD1-driven NICD signaling promoted the differentiation and functions of Th1 and Th17 cells and amplified the cascade of aGVHD. Additionally, the expression level of OTUD1 is positively correlated with Notch2 target genes (Hes1, Hes5, Hey1, HeyL) in aGVHD patients. Moreover, screening performed in the present study identified dapagliflozin as an inhibitor targeting the OTUD1/NICD axis. Dapagliflozin administration significantly prolonged the survival of aGVHD mice. Taken together, the current work not only characterized a previously undiscovered role of OTUD1 in T cell-mediated allogeneic responses, and identified OTUD1 as a novel deubiquitinase of Notch2, but also revealed a promising therapeutic strategy to target OTUD1 for the alleviation of aGVHD.