Rpn11

Rpn11, also known as regulatory particle non-ATPase 11, is a zinc-dependent deubiquitinating enzyme that is a component of the 19S regulatory particle lid of the 26S proteasome in eukaryotes. In humans the ortholog is PSMD14; in budding yeast it is RPN11. It belongs to the JAMM/MPN+ family of metalloproteases and functions to remove ubiquitin chains from substrates as they are prepared for degradation.

Rpn11’s deubiquitinating activity is tightly coordinated with substrate recognition and unfolding by the 19S regulatory particle, and it acts before the substrate is translocated into the 20S core particle. This step enables recycling of ubiquitin and is essential for efficient proteolysis. The enzyme’s catalytic activity depends on the JAMM motif, which coordinates a zinc ion at the active site.

Structurally, Rpn11 is part of the 19S lid and forms a functional complex with Rpn8. The catalytic domain containing the JAMM motif is conserved across eukaryotes, and PSMD14 serves as its human homolog. The protein’s activity is integral to maintaining cellular protein homeostasis, as impairment of Rpn11 function disrupts proteasome-mediated degradation and leads to accumulation of polyubiquitinated substrates.

Biological and clinical significance: Rpn11 is essential for proteostasis and viability in many organisms. Because of its central role in ubiquitin processing, it is a potential therapeutic target; inhibitors that block Rpn11 DUB activity, such as Capzimin, can induce proteotoxic stress selectively in cancer cells and are studied as a cancer treatment strategy.