PSME1

PSME1 (PA28alpha/REGalpha) is an IFN-gamma-inducible proteasome regulator that assembles into a heptameric, barrel-shaped activator which docks onto the alpha-ring face of the 20S proteasome to stimulate peptide hydrolysis and reshape cleavage patterns (PMID:8610016, PMID:9403698). Its crystal structure reveals a central channel that widens toward the proteasome-binding surface, providing a structural basis for opening the alpha-subunit gate to permit substrate and product passage (PMID:9403698). The principal characterized cellular role is enhancement of MHC class I antigen presentation: PA28alpha alone activates 20S peptide hydrolysis in vitro and, at IFN-gamma-inducible levels, boosts presentation of viral epitopes, while the PA28alpha/beta (PSME1/PSME2) heteromer augments epitope presentation without altering 20S subunit composition and is selectively required for processing particular antigens such as the melanoma antigen TRP2 (PMID:8610016, PMID:11169410, PMID:11689430). PA28alpha/beta associates with proteasomes throughout assembly and maturation and contributes to ATP-dependent proteolysis via hybrid proteasomes (PMID:11689430, PMID:11745344). Beyond antigen processing, PSME1-dependent proteasome activity controls protein homeostasis and the stability of specific factors in disease contexts: it supports myeloma cell proliferation and proteasome-inhibitor sensitivity (PMID:33318477), drives breast cancer invasion by lowering CDK15 (PMID:31824858), stabilizes HBV core protein to sustain viral transcription (PMID:39281837), limits Wnt/beta-catenin signaling by reducing beta-catenin levels (PMID:34838695), and promotes ABCA1 degradation to impair podocyte cholesterol efflux in diabetic kidney disease (PMID:38228909).

1. 1996 High

   Established that PA28alpha is not merely an in vitro proteasome activator but functions in cells to enhance antigen processing, answering whether its biochemical activity has an immunological consequence.

   Evidence Transfection of PA28alpha into antigen-expressing fibroblasts with CTL recognition readout and in vitro peptide-hydrolysis assay

   PMID:8610016

   Open questions at the time

   • Did not resolve the structural mechanism of 20S activation
   • Limited to two viral epitopes; generality across the epitope repertoire unaddressed
2. 1997 High

   Defined the heptameric architecture and central channel of PA28alpha, providing a structural model for how REG binding opens the proteasome alpha-ring gate.

   Evidence X-ray crystallography of recombinant human REGalpha heptamer at 2.8 Å

   PMID:9403698

   Open questions at the time

   • Structure of the PA28-20S complex not determined
   • Conformational change in alpha-subunits inferred rather than directly visualized
3. 2000 High

   Showed that the PA28alpha/beta heteromer enhances presentation without changing 20S subunit composition, distinguishing a gating/processing effect from a change in catalytic subunit makeup.

   Evidence Stable co-transfection of PA28alpha and PA28beta with subunit composition analysis and CTL recognition assay

   PMID:11169410

   Open questions at the time

   • Mechanism by which cleavage specificity is altered not defined
   • Tested for a single epitope
4. 2001 High

   Genetic loss-of-function established that PA28alpha/beta is required for processing specific antigens but dispensable for general antigen presentation, and linked it to ATP-dependent (hybrid) proteasome activity.

   Evidence PA28alpha/PA28beta double-knockout mice with proteolytic activity and CTL antigen presentation assays

   PMID:11689430

   Open questions at the time

   • Why only certain antigens depend on PA28 unresolved
   • Contribution of hybrid versus capped proteasomes not quantified
5. 2001 Medium

   Determined when PA28alpha/beta engages the proteasome, showing association from precursor assembly through maturation rather than only with mature particles.

   Evidence Co-immunoprecipitation of PA28alpha/beta with proteasome precursor and mature complexes in dendritic cells

   PMID:11745344

   Open questions at the time

   • Single method (co-IP) without reciprocal or structural confirmation
   • Functional significance of precursor association untested
6. 2016 Medium

   Extended PA28 function to diabetic microvascular pathology, showing PA28-20S activity drives inflammatory gene expression under high glucose.

   Evidence PA28alpha/beta double-knockout mice in STZ-diabetes model plus peptide inhibitors of PA28-20S binding and OPN/MCP-1 readouts

   PMID:27830089

   Open questions at the time

   • Direct substrates linking PA28 activity to OPN/MCP-1 expression unidentified
   • Single lab
7. 2019 Medium

   Identified CDK15 as a downstream target whose PA28-dependent down-regulation promotes tumor invasion, connecting PA28 activity to a defined oncogenic phenotype.

   Evidence siRNA knockdown of PA28alpha, PA28beta and beta5i in breast cancer cells with invasion assays and CDK15 protein measurement

   PMID:31824858

   Open questions at the time

   • Whether CDK15 is a direct proteasome substrate not established
   • Single lab
8. 2020 Medium

   Demonstrated a proliferation and drug-resistance role in multiple myeloma, where PA28alpha sets proteasomal load and dependence.

   Evidence PA28alpha knockdown in myeloma cell lines with proteasome activity, growth, and proteasome-inhibitor sensitivity assays

   PMID:33318477

   Open questions at the time

   • Molecular basis of the homeostatic shift away from proteasome dependence unclear
   • Single lab, cell-line based
9. 2021 Medium

   Linked PSME1/2 proteasome activity to bone homeostasis through control of beta-catenin levels and Wnt signaling.

   Evidence Recombinant PSME1/2 treatment of osteoblast/osteoclast cultures, beta-catenin level/localization assays, carfilzomib, and OVX mouse micro-CT

   PMID:34838695

   Open questions at the time

   • Whether beta-catenin is a direct PA28-proteasome substrate not shown
   • Single lab
10. 2021 Medium

    Probed PA28alpha's role in proteostasis and aging, showing it can sustain anti-aggregation capacity yet paradoxically lower PA28-dependent proteasome capacity in some tissues.

    Evidence Transgenic PA28alpha-overexpressing mice with aggregation assays, proteasome activity, and behavioral testing across ages

    PMID:33720528

    Open questions at the time

    • Mechanism behind tissue-specific and paradoxical proteasome effects unresolved
    • Sex-specific findings not generalized
11. 2023 Medium

    Revealed a substrate-stabilizing function in viral infection, where PSME1 binds HBV core protein and protects it from 26S degradation.

    Evidence APEX2 proximity labeling and co-IP of PSME1 with HBc, plus PSME1 knockdown measuring HBc stability and HBV transcription

    PMID:39281837

    Open questions at the time

    • How a 20S activator shields a substrate from 26S degradation mechanistically unclear
    • Single lab
12. 2024 Medium

    Defined a PA28alpha/ABCA1/cholesterol efflux axis in podocytes regulated by CCDC92, connecting PA28-mediated degradation to lipid handling in diabetic kidney disease.

    Evidence Podocyte-specific Ccdc92 knockout mice with ABCA1 degradation, cholesterol efflux, and PA28alpha activity assays

    PMID:38228909

    Open questions at the time

    • Direct physical/biochemical link between PA28alpha and ABCA1 degradation not fully defined
    • Single lab

• How PA28alpha switches between activating proteasomal degradation of some targets and stabilizing others, and what dictates its substrate/epitope selectivity, remains unresolved.
• No structure of the PA28-20S or PA28-substrate complex in the corpus
• No unifying rule for substrate/epitope selection across the diverse disease contexts