PSMC6

PSMC6 is an ATPase subunit of the 19S regulatory particle of the 26S proteasome that is required for full proteasomal chymotrypsin-like activity and, consequently, for the protein-degradation function on which cancer cells depend (PMID:28958990). Genome-wide CRISPR screening in multiple myeloma established that loss of PSMC6 confers resistance to the proteasome inhibitor bortezomib by blunting its inhibition of chymotrypsin-like activity, a property shared across the PSMC ATPase group (PMID:28958990). In ovarian carcinoma, PSMC6 depletion causes accumulation of ubiquitinated proteins and reduces growth and clonogenicity, and it suppresses ERK1/2 phosphorylation through upregulation of DUSP6 while increasing cisplatin sensitivity—an effect distinct from direct 20S or 19S inhibition, indicating that targeting the ATPase subunit itself perturbs proteasome output through a separable route (PMID:40083690). PSMC6 also intersects survival and growth signaling beyond the proteasome: it promotes apoptosis by inhibiting PI3K/AKT signaling, with PI3K activation rescuing PSMC6-induced apoptosis and normalizing p53, cyclin D1, and cleaved caspase-3/9 (PMID:32017075), and it is directly bound and stabilized by the SYT4 C2B domain, an interaction that activates Wnt/β-catenin signaling in gastric carcinoma (PMID:41281742). A lower-confidence study additionally implicates PSMC6 as a driver of lymphocytic infiltration in a Sjögren's syndrome model (PMID:36599955).

1. 2017 High

   Established that PSMC6 is functionally required for proteasome chymotrypsin-like activity and therefore for sensitivity to the proteasome inhibitor bortezomib, defining it as a genetic determinant of drug response.

   Evidence Genome-wide CRISPR knockout screen with secondary sgRNA validation and individual knockout plus proteasome activity assay in multiple myeloma cells

   PMID:28958990

   Open questions at the time

   • Does not resolve how PSMC6 ATPase activity mechanistically couples to chymotrypsin-like 20S catalysis
   • Resistance phenotype shared across PSMC1-6 leaves PSMC6-specific contribution undefined
2. 2020 Medium

   Connected PSMC6 to apoptotic and cell-cycle control by showing it promotes apoptosis through inhibition of PI3K/AKT signaling, linking the proteasome subunit to a survival pathway.

   Evidence In vivo PSMC6 knockout in an OVX osteoporosis mouse model and in vitro overexpression/inhibition with caspase and PI3K-activator rescue readouts

   PMID:32017075

   Open questions at the time

   • Mechanism linking proteasome ATPase activity to PI3K suppression not defined
   • Single-lab findings without independent replication
   • Whether effect depends on proteasome catalytic function is untested
3. 2023 Low

   Implicated PSMC6 as a driver of immune cell infiltration and inflammation in autoimmune disease, extending its role beyond cancer cell biology.

   Evidence PSMC6 knockdown in a primary Sjögren's syndrome mouse model with histology, cytokine measurement, and Treg flow cytometry

   PMID:36599955

   Open questions at the time

   • Limited mechanistic detail reported; molecular pathway connecting PSMC6 to infiltration unknown
   • Single lab, in vivo knockdown without rescue
   • No link established to proteasome activity in immune cells
4. 2025 Medium

   Showed that PSMC6 depletion perturbs proteostasis and downstream signaling in a manner distinct from canonical proteasome inhibition, revealing the ATPase subunit as a separable proteasome-targeting node.

   Evidence CRISPR loss-of-function screen and siRNA knockdown in ovarian carcinoma with ubiquitin/pERK1/2/DUSP6 immunoblots, clonogenic and spheroid assays, and proteasome-inhibitor sensitivity comparison

   PMID:40083690

   Open questions at the time

   • How loss of an ATPase subunit selectively engages DUSP6/ERK1/2 is unresolved
   • Single-lab study without orthogonal in vivo confirmation
5. 2025 Medium

   Identified a direct protein partner of PSMC6, demonstrating that SYT4 binds and stabilizes PSMC6 to activate Wnt/β-catenin signaling.

   Evidence IP-MS, reciprocal Co-IP, GST pull-down mapping the SYT4 C2B domain, and TOP/FOP reporter plus tumor models in gastric carcinoma

   PMID:41281742

   Open questions at the time

   • Mechanism by which SYT4 binding stabilizes PSMC6 protein not defined
   • Link between PSMC6 and β-catenin activation downstream of stabilization unclear
   • Single-lab finding

• How PSMC6's core ATPase function within the 19S particle mechanistically gives rise to its diverse downstream effects on PI3K/AKT, ERK1/2-DUSP6, and Wnt/β-catenin signaling remains unresolved.
• No structural model linking PSMC6 to specific substrate degradation events
• No unified mechanism connecting proteasome subunit loss to the multiple signaling pathways reported
• Substrate(s) of the PSMC6-containing proteasome relevant to these pathways unidentified