Anti-JOSD2 (aa 36-85) polyclonal antibody

The functional diversity of deubiquitinating enzymes (DUBs) is not well understood. The MJD family of DUBs consists of four cysteine proteases that share a catalytic "Josephin" domain. The family is named after the DUB ATXN3, which causes the neuro-degenerative disease Machado-Joseph disease. The two closely related Josephin domain-containing (JosD) proteins 1 and 2 consist of little more than the Josephin domain. To gain insight into the properties of Josephin domains, we investigated JosD1 and JosD2. JosD1 and JosD2 were found to differ fundamentally in many respects. In vitro, only JosD2 can cleave ubiquitin chains. In contrast, JosD1 cleaves ubiquitin chains only after it is monoubiquitinated, a form of posttranslational-dependent regulation shared with ATXN3. A significant fraction of JosD1 is monoubiquitinated in diverse mouse tissues. In cell-based studies, JosD2 localizes to the cytoplasm whereas JosD1 preferentially localizes to the plasma membrane, particularly when ubiquitinated. The membrane occupancy by JosD1 suggests that it could participate in membrane-dependent events such as cell motility and endocytosis. Indeed, time-lapse imaging revealed that JosD1 enhances membrane dynamics and cell motility. JosD1 also influences endocytosis in cultured cells by increasing the uptake of endocytic markers of macropinocytosis while decreasing those for clathrin- and caveolae-mediated endocytosis. Our results establish that two closely related DUBs differ markedly in activity and function and that JosD1, a membrane-associated DUB whose activity is regulated by ubiquitination, helps regulate membrane dynamics, cell motility, and endocytosis.

Ubiquitination is known as important post-translational modification in cancer-related pathways. Human deubiquitinases (DUBs), with functions of modulating the ubiquitination process, are a family with about 100 proteins. They mainly function by cutting ubiquitin chains of the substrates. The Machado-Joseph domain-containing proteases (MJDs) is one of the sub-families of DUBs, consisting of four members, namely, Ataxin-3, Ataxin-3L, JOSD1, and JOSD2. Recent studies have provided new insights into biological functions of MJDs in the progression of Machado-Joseph disease or cancer diseases. In this review, we summarized the cellular functions and regulatory mechanisms of MJDs in Machado-Joseph disease and cancer pathways. Furthermore, we summarized MJDs genetic alterations in different human cancers by exploring the public databases (cBioportal). The aim of this review is to provide a comprehensive account based on our current knowledge about emerging insights into MJDs in physiology and disease, which might shed light on fundamental biological questions and promise to provide a potential target for therapeutic intervention.