Josd2-flox Mouse

Josd2, short for Josephin domain-containing protein 2, is a deubiquitinating enzyme (DUB). DUBs maintain the stability of substrate proteins, and Josd2 is involved in various biological processes through regulating protein deubiquitination. It is associated with multiple pathways such as those related to calcium handling, tumor-suppressor regulation, and glucose metabolism, and is of great importance in understanding cardiac pathophysiology and cancer development [1-7].

In cardiac studies, Josd2 gene knockout in mice aggravated cardiac dysfunction and hypertrophy, while overexpression prevented angiotensin II-induced cardiac hypertrophy. It was found that Josd2 stabilizes sarco/endoplasmic reticulum calcium ATPase 2a (SERCA2a) by deubiquitination, improving calcium handling [1].

In cancer research, depletion of Josd2 in NSCLC cells significantly impeded their growth in vivo. Mechanistically, Josd2 restricts the kinase activity of LKB1, a tumor suppressor, by removing K6-linked polyubiquitination [2]. In cholangiocarcinoma, depletion of Josd2 promoted YAP/TAZ proteasomal degradation and impeded cancer cell proliferation in vitro and in vivo [3]. Also, in AML, reconstitution of Josd2 in AML cells inhibited cell viability and induced apoptosis by blocking PKM2 nuclear localization [4].

In conclusion, Josd2 is a crucial deubiquitinating enzyme with diverse functions. Studies using Josd2 knockout mouse models have revealed its significance in cardiac hypertrophy, heart failure, and multiple cancers. Understanding Josd2's role can potentially provide new therapeutic targets for these disease areas.