Rpn11s

Rpn11s are proteasome-associated deubiquitinases that contain a JAMM/MPN domain and function as zinc-dependent metalloproteases within the 19S regulatory particle of the 26S proteasome. In eukaryotes the catalytic deubiquitinase activity is provided by Rpn11, with the human ortholog encoded by PSMD14. Rpn11 resides in the lid of the 19S regulatory particle and directly engages substrates as they are unfolded and prepared for entry into the 20S core particle.

Rpn11s cleave isopeptide bonds linking ubiquitin to substrate or between ubiquitin units, trimming polyubiquitin chains and recycling ubiquitin before degradation. Their deubiquitination activity is tightly coupled to substrate translocation and is essential for efficient proteolysis. The catalytic mechanism relies on a JAMM/MPN metalloprotease motif that coordinates a zinc ion at the active site, enabling hydrolysis of the isopeptide bond.

Loss or impairment of Rpn11 function leads to accumulation of ubiquitinated proteins and proteasome dysfunction, with cellular consequences such as impaired cell cycle progression and increased sensitivity to proteotoxic stress. Rpn11 activity can be modulated by proteasome conformational changes and interactions with other 19S subunits, reflecting its integration into the broader proteasome regulatory network.

Because of its central role, Rpn11 has attracted interest as a therapeutic target. Small molecules like capzimin inhibit Rpn11 DUB activity and can impair proteasome function, showing activity in preclinical cancer models and highlighting the potential for selective proteasome deubiquitinase inhibition.

Rpn11s are evolutionarily conserved in eukaryotes, with gene names including RPN11 in yeast and PSMD14 in humans, underscoring their status as fundamental components of the ubiquitin–proteasome system.