PSMD10

PSMD10/gankyrin is an oncoprotein that drives tumor cell survival, proliferation, and autophagy through proteasome-independent activities in hepatocellular, colon, and prostate cancers (PMID:25905985, PMID:35378311). In the cytoplasm it physically associates with ATG7 in a manner enhanced by nutrient deprivation, and it also translocates to the nucleus where it co-binds with HSF1 on the ATG7 promoter to upregulate ATG7 and promote autophagy (PMID:25905985); this autophagy-promoting function requires PSMD10 homodimerization for the ATG7 interaction (but not for binding ATG12) and is antagonized by the bacterial effector NleE, which traps PSMD10 as a monomer (PMID:34254583). PSMD10 supports survival signaling by enabling TNF-α-induced phosphorylation and transcriptional activation of NFκB (RELA), thereby sustaining anti-apoptotic target genes (TNFAIP3, BIRC2, BIRC3, XIAP), and by transcriptionally regulating β-catenin and RB1 (PMID:35378311). In non-parenchymal liver and intestinal/myeloid cells it promotes tumorigenesis via STAT3 activity and IL-6 production (PMID:31576540), and it physically interacts with GRP78 to modulate ER stress-mediated hepatic apoptosis (PMID:34666830). Its expression is transcriptionally upregulated by JMJD2A/ETV1 in prostate cancer (PMID:28883898), and a druggable pocket centered on residues K116 and R41 accommodates the EEVD peptide, the partner CLIC1, and the drug doxorubicin (PMID:34953804).

1. 2015 High

   Established that PSMD10 acts outside the proteasome by directly coupling to the autophagy machinery, resolving how this oncoprotein promotes autophagy in liver cancer.

   Evidence Co-IP, nuclear fractionation, ChIP, and promoter reporter with loss-of-function in HCC cells

   PMID:25905985

   Open questions at the time

   • Does not define the structural basis of the ATG7 interaction
   • Does not establish how nuclear translocation is triggered
2. 2016 Medium

   Identified upstream transcriptional drivers of PSMD10, showing its expression is induced by JMJD2A/ETV1 and contributes to prostate cancer cell growth.

   Evidence JMJD2A transgenic mice, siRNA knockdown with proliferation assay, co-expression and overexpression cooperation with YAP1

   PMID:28883898

   Open questions at the time

   • No direct binding of JMJD2A/ETV1 to the PSMD10 promoter demonstrated
   • Mechanism of YAP1 cooperation not defined
3. 2019 Medium

   Defined the cell-type context of PSMD10 oncogenic function, showing tumorigenesis depends on its action in non-parenchymal/myeloid cells through STAT3 and IL-6.

   Evidence Conditional knockout mouse models in DEN hepatocarcinogenesis and colitis-associated cancer, STAT3 and cytokine readouts

   PMID:31576540

   Open questions at the time

   • Direct molecular link between PSMD10 and STAT3 activation not established
   • Review/book-chapter summary limits primary-data resolution
4. 2019 Low

   Extended PSMD10 function beyond cancer, implicating it in neuronal differentiation via the β-catenin/Ngn1 pathway.

   Evidence Overexpression in human neural progenitor cells with microarray profiling and differentiation assays

   PMID:31474027

   Open questions at the time

   • No direct binding or epistasis for the β-catenin/Ngn1 mechanism
   • Relies solely on overexpression and pathway inference
5. 2020 Low

   Linked PSMD10 to cell cycle progression, showing it elevates cyclins and phosphorylates STAT3 and Rb1 in liver cancer cells.

   Evidence Overexpression/knockdown in liver cancer cells, western blot, flow cytometry, xenograft

   PMID:32437796

   Open questions at the time

   • No direct binding mechanism established
   • Single-lab, single overexpression/KD approach
6. 2021 High

   Resolved the structural requirement for PSMD10's autophagy function and identified a pathogen that subverts it, showing homodimerization is needed for ATG7 binding and that NleE locks PSMD10 as an inactive monomer.

   Evidence In-cell genetically incorporated crosslinkers, pairwise chemical crosslinking, Co-IP, and autophagosome formation assays

   PMID:34254583

   Open questions at the time

   • Does not explain why ATG12 binding is dimerization-independent
   • Physiological context of NleE-driven autophagy suppression in infection not fully mapped
7. 2021 Medium

   Added an ER-stress dimension, showing PSMD10 interacts with GRP78 to accelerate homocysteine-induced hepatic apoptosis.

   Evidence Co-IP, siRNA knockdown with ER-stress/apoptosis marker western blots, miR-212-5p luciferase reporter

   PMID:34666830

   Open questions at the time

   • Single lab with limited orthogonal validation
   • Direct effect of the GRP78 interaction on UPR signaling not mechanistically dissected
8. 2021 Medium

   Mapped a druggable pocket on PSMD10 and identified it as a doxorubicin target, defining residues that govern partner binding.

   Evidence Virtual screening, MST, SPR, ITC, limited trypsinolysis, and mutational mapping of K116/R41

   PMID:34953804

   Open questions at the time

   • Functional consequence of doxorubicin binding on PSMD10 oncogenic activity not established
   • Cellular CLIC1/EEVD interplay at this pocket not validated in cells
9. 2022 Medium

   Connected PSMD10 to NFκB survival signaling, showing it is required for RELA activation and maintenance of anti-apoptotic gene expression under TNF-α.

   Evidence siRNA knockdown, phospho-NFκB western blot, qPCR of target genes, apoptosis assays in TNF-α-treated colon cancer cells

   PMID:35378311

   Open questions at the time

   • Direct molecular step by which PSMD10 promotes RELA phosphorylation not identified
   • Single-lab study
10. 2025 Low

    Implicated viral oncogenesis in PSMD10 regulation, showing EBV EBNA1 upregulates PSMD10 transcription.

    Evidence EBNA1 plasmid transfection and real-time PCR in HeLa cells

    PMID:40771905

    Open questions at the time

    • Single method (qPCR) with no mechanistic detail on EBNA1-driven activation
    • No demonstration that EBNA1 acts directly on the PSMD10 promoter

• How PSMD10's proteasome-independent oncogenic activities are structurally and temporally coordinated with its proteasome-assembly chaperone role remains unresolved.
• No structural model integrating ATG7, GRP78, CLIC1, and NFκB-related interactions
• Direct biochemical link between PSMD10 and the kinases/signaling nodes it activates is undefined