Josephin domain-containing protein 2 (JOSD2)

Josephin domain-containing protein 2 (JOSD2) is a cysteine-type deubiquitinating enzyme that selectively cleaves polyubiquitin chains with K11, K48, and K63 linkages[2][5]. It belongs to the Machado-Josephin Domain (MJD) subfamily and contains a single Josephin domain but lacks extended regulatory regions seen in related proteins such as ataxin-3[2]. JOSD2 regulates the ubiquitin-dependent turnover and stability of key oncogenic and metabolic proteins, including mutant KRAS (implicated in colorectal cancer), LKB1 (in lung cancer), metabolic enzymes, and Hippo pathway effectors. Its high expression is associated with poor outcomes and tumor progression across several cancers, and pharmacological inhibition or RNAi-mediated silencing of JOSD2 suppresses tumor growth in preclinical models, making it a promising therapeutic target[1][3][5]. It may also play roles in certain inherited neurodegenerative diseases (e.g., Machado-Joseph Disease)[5].

Other names

Josephin-2JOSD2SBBI54JOS2josephin-2GC19M055702Q8TAC2

Inhibition of JOSD2 leads to increased polyubiquitination and proteasomal degradation of its substrates (e.g., KRAS mutants), suppressing tumor growth[3]. Enzymatic removal of ubiquitin from target proteins increases their stability and alters signaling pathways[2][3].