Proteasome activator complex subunit 3 (PSME3)

Proteasome activator complex subunit 3 (PSME3, also known as PA28-gamma or REG-gamma) is a regulatory protein that forms a homoheptameric or homohexameric ring complex (the 11S regulator) and binds to the 20S proteasome core particle, thereby modulating its proteolytic activity. PSME3 preferentially activates the proteasome’s trypsin-like activity but inhibits other catalytic activities. It plays important roles in the regulation of protein degradation, cell cycle progression, apoptosis, and antigen processing, as well as regulation of chromatin and nuclear structure. PSME3 interacts with crucial cell cycle regulators (including p53/TP53 and Mdm2), transcriptional regulators, and several signaling pathways. It is overexpressed in several human cancers and is implicated in tumorigenesis and metastasis, making it an emerging target of interest in oncology. PSME3 also has roles in immune modulation, muscle and bone differentiation, and other cell fate decisions, with both proteasome-dependent and -independent functions.

Other names

PA28-gammaREG-gammaPA28GKi11S regulator complex subunit gammaProteasome activator 28 subunit gammaActivator of multicatalytic protease subunit 3Ki nuclear autoantigenHEL-S-283REG-GAMMAProteasome (prosome, macropain) activator subunit 3 (PA28 gamma; Ki)

Drugs targeting the proteasome (e.g., bortezomib) generally inhibit proteolytic activity of the core proteasome; these do not specifically target PSME3 but can affect complexes in which PSME3 acts as a cap/regulator. There are no established mechanisms for drugs acting specifically on PSME3 at present.