Abstract
Background & aims: Acute pancreatitis (AP) results in localized pancreatic injury or systemic inflammatory responses, contributing to high morbidity and mortality worldwide. Acinar cell death and inflammation are critical key drivers of AP progression. Some deubiquitinases (DUBs), which regulate the stability and/or activity of substrate proteins, may play a role in the development of AP. Here, we aimed to investigate how Josephin domain-containing protein 2 (JOSD2) involved in AP progression. Methods: JOSD2 expression was assessed in mouse pancreatic tissues with cerulein-induced AP. Cerulein- or L-arginine-induced AP models were constructed in whole-body JOSD2 knockout (JOSD2-/-) and wild-type (WT) mice. Bone marrow JOSD2-/- chimeric mice were generated and subjected to cerulein-induced AP. In vitro studies were conducted on primary acinar cells isolated from JOSD2-/- and WT mice. Results: JOSD2 expression was upregulated in the pancreas of cerulein-treated mice, and the loss of JOSD2 offered protection against cerulein- or L-arginine-induced AP. Bone marrow transplantation assay revealed that myeloid JOSD2 was not involved in the progression of cerulein-induced AP. In vitro studies, primary acinar cells isolated from JOSD2-/- mice demonstrated increased resistance to cerulein-induced injury and inflammation. Proliferating cell nuclear antigen (PCNA) was identified as a key substrate of JOSD2. JOSD2 selectively removes K63-linked polyubiquitin chains from PCNA at the K164 site. The protective effects of JOSD2 deficiency on DNA damage and acinar cell death were reversed by the PCNA inhibitor PCNA-I1. Conclusions: JOSD2 regulates AP progression via PCNA-mediated DNA damage response and may serve as a promising therapeutic target for AP treatment.