Ubiquitin carboxyl-terminal hydrolase MINDY-2 (MINDY2)

Ubiquitin carboxyl-terminal hydrolase MINDY-2 (MINDY2) is a member of the MINDY family of deubiquitinating enzymes, characterized by highly specific cleavage of K48-linked polyubiquitin chains—the primary signal for targeting proteins to the proteasome for degradation. MINDY2’s catalytic core recognizes both ubiquitin chain length and linkage type, utilizing a non-canonical Cys-His-Thr triad for catalysis. It modulates protein stability by removing K48-linked ubiquitin from substrates such as ACTN4, thereby preventing proteasomal degradation. MINDY2 is implicated in cancer biology, particularly pancreatic cancer, where its overexpression promotes proliferation, migration, epithelial-mesenchymal transition (EMT), immune infiltration, and angiogenesis by stabilizing ACTN4 and activating the PI3K/AKT/mTOR signaling pathway. Genetically, MINDY2 is related to FAM63B and possesses regions for ubiquitin binding and peptidase activity. Regulation of its catalytic activity involves structural changes (e.g., a Cys-loop), and its cellular functions extend to chromatin remodeling and protein turnover. MINDY2 is a considered a novel therapeutic target and biomarker for cancer, although direct inhibitors are not yet clinically available.

Other names

MINDY lysine 48 deubiquitinase 2FAM63BKIAA1164Deubiquitinating enzyme MINDY-2Protein FAM63Bfamily with sequence similarity 63 member B

Drugs (potential/future) could act as inhibitors or modulators of deubiquitinase activity, specifically blocking the removal of K48-linked ubiquitin chains on target proteins