UBLCP1 (ubiquitin-like domain containing CTD phosphatase 1) is a serine/threonine phosphatase that negatively regulates 26S proteasome activity through dephosphorylation of regulatory particle components 1. The protein selectively binds to the 19S regulatory particle via interaction with the PSMD2/RPN1 subunit, where it dephosphorylates PSMC2/RPT1, impairing its ATPase activity and disrupting 26S proteasome assembly 1. Originally identified as a C-terminal domain phosphatase with capacity to dephosphorylate RNA polymerase II 2, UBLCP1 shows higher expression in rapidly dividing and tumor tissues 2. Disease relevance includes genetic associations with tuberculosis susceptibility 34 and psoriatic arthritis 5. Notably, an autism-associated UBLCP1 deletion mutation causes loss of phosphatase domain function, resulting in paradoxical proteasome hyperactivation, decreased ubiquitinated protein levels, and dysregulation of proteasome subunit expression 6. Selective UBLCP1 inhibitors have been developed with IC₅₀ values of 1.0 μM and demonstrate therapeutic potential by upregulating nuclear proteasome activity in cells 7. These findings establish UBLCP1 as a critical regulator of proteolysis with relevance to neurodevelopmental and immune-related diseases.