PSME2

PSME2 (PA28β) is a subunit of the interferon-γ-inducible PA28αβ proteasome activator, which binds both ends of the 20S proteasome to form 'hybrid proteasomes' that contribute to ATP-dependent protein degradation and to the processing of specific antigens such as the melanoma TRP2-derived peptide, while being dispensable for general antigen presentation (PMID:11689430). PA28β does not function autonomously: its apparent activity in enhancing MHC class I antigen presentation reflects its incorporation into PA28αβ heterodimers rather than independent action (PMID:10781831). PA28-dependent chymotrypsin-like proteasome activity is negatively regulated by Naa10p, which physically associates with PA28β and, through it, with PA28α, in a manner independent of Naa10p acetyltransferase activity (PMID:23624078). Binding of PA28 to the 20S proteasome is required for high-glucose-induced upregulation of OPN and MCP-1 in renal mesangial cells, linking the activator to diabetic microvascular injury (PMID:27830089). In cancer and epithelial-barrier contexts, PSME2 suppresses autophagy and restrains it through BNIP3 and the IL-6/STAT3 axis, thereby promoting tumor cell survival and invasion and disrupting intestinal barrier integrity (PMID:34779489, PMID:40404117, PMID:41211066), and it modulates gastric cancer invasiveness at least partly by repressing CLIC1 (PMID:22173998).

1. 2000 Medium

   Established that PA28β cannot drive proteasome-dependent antigen presentation on its own, resolving whether the two PA28 subunits act independently.

   Evidence Stable transfection of PA28β alone versus PA28αβ in mouse B8 cells with reciprocal immunoprecipitation and an MHC class I antigen presentation assay for the MCMV pp89 epitope

   PMID:10781831

   Open questions at the time

   • Does not quantify the stoichiometry of PA28αβ assembly required for activity
   • Single epitope tested in one cell system
2. 2001 High

   Defined the in vivo role of PA28αβ by showing it forms hybrid proteasomes contributing to proteolysis and is specifically required for processing certain antigens but not for general antigen presentation.

   Evidence PA28α/β double-knockout mice with biochemical proteolytic activity assays, ovalbumin and TRP2 antigen presentation assays, and influenza A infection

   PMID:11689430

   Open questions at the time

   • Does not define which antigen structural features make processing PA28αβ-dependent
   • Mechanism by which hybrid proteasomes enhance proteolysis not resolved at the structural level
3. 2013 High

   Identified a negative regulator of the activator by showing Naa10p binds PA28β and suppresses PA28-dependent chymotrypsin-like activity independently of its acetyltransferase function.

   Evidence Co-immunoprecipitation in cancer cells, cell-free reconstitution with purified proteins, proteasome chymotrypsin-like activity assay, and an acetyltransferase-dead Naa10p mutant

   PMID:23624078

   Open questions at the time

   • Structural basis of Naa10p–PA28β interaction unknown
   • Physiological contexts where this regulation operates not defined
4. 2012 Medium

   Connected PSME2 to cancer cell invasion by placing CLIC1 downstream as a mediator, addressing how the activator influences tumor behavior.

   Evidence siRNA knockdown and overexpression of PA28β in gastric cancer cells, Transwell invasion assays, 2D-gel/MS proteomics, and CLIC1 knockdown rescue

   PMID:22173998

   Open questions at the time

   • How PSME2 represses CLIC1 mechanistically is not shown
   • Single lab and cancer type
5. 2016 Medium

   Linked PA28–20S binding to a disease phenotype by demonstrating it is required for high-glucose-induced OPN/MCP-1 expression and diabetic microvascular injury.

   Evidence PA28α/β double-KO STZ-diabetic mice, peptide inhibition of PA28–20S binding in mesangial cells and pericytes, and immunohistochemistry for OPN/MCP-1

   PMID:27830089

   Open questions at the time

   • Substrates degraded by PA28-bound proteasome to drive OPN expression not identified
   • Single lab
6. 2025 Medium

   Consolidated PSME2 as a suppressor of autophagy across cancer and epithelial contexts, defining BNIP3 and IL-6/STAT3 as the pathways through which it restrains autophagy to promote survival, invasion, and barrier disruption.

   Evidence siRNA knockdown of PSME2 in ccRCC, ESCC, and LPS-treated colonic cells with autophagy readouts (LC3, p62, TEM), STAT3 inhibitor WP1066 and chloroquine rescue, and in vivo xenograft and DSS-colitis models

   PMID:34779489 PMID:40404117 PMID:41211066

   Open questions at the time

   • Whether autophagy suppression depends on PSME2's proteasome-activator function is not established
   • Direct molecular link between PSME2 and BNIP3 or IL-6/STAT3 not defined

• How PSME2's canonical role as a 20S proteasome activator mechanistically connects to its autophagy-suppressing and invasion-modulating activities in disease remains unresolved.
• No structural model linking proteasome activation to autophagy regulation
• Direct degradation substrates underlying disease phenotypes not identified
• Whether PA28α is co-required for the cancer/epithelial phenotypes untested