PSMD14/POH1/Rpn11 plays a crucial role in cellular homeostasis. PSMD14 is a structural subunit of the lid subcomplex of the proteasome 19S regulatory particle with constitutive deubiquitinase activity. Canonically, PSMD14 removes the full ubiquitin chains with K48-linkages by hydrolyzing the isopeptide bond between the substrate and the C-terminus of the first ubiquitin, a crucial step for the entry of substrates into the catalytic barrel of the 20S proteasome and their subsequent degradation, all in context of the 26S proteasome. However, more recent discoveries indicate PSMD14 DUB activity is not only coupled to the translocation of substrates into the core of 20S proteasome. During the assembly of the lid, activity of PSMD14 has been detected in the context of the heterodimer with PSMD7. Additionally, assembly of the lid subcomplex occurs as an independent event of the base subcomplex and 20S proteasome. This feature opens the possibility that the regulatory particle, free lid subcomplex or the heterodimer PSMD14-PSMD7 might play other physiological roles including a positive function on protein stability through deubiquitination. Here we discuss scenarios that could enhance this PSMD14 non-canonical pathway, the potential impact in preventing degradation of substrates by autophagy highlighting the main findings that support this hypothesis. Finally, we discuss why this information should be investigated in biomedicine specifically with focus on cancer progression to design new therapeutic strategies against the lid subcomplex and the heterodimer PSMD14-PSMD7, highlighting PSMD14 as a druggable target for cancer therapy.

Original languageEnglish
Article number110490
JournalCellular Signalling
StatePublished - 2023

Bibliographical note

Funding Information:
This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico of Chile (FONDECYT) No. 1211261 to PVB, No. 3200573 to HAB, No. 1200499 to EM; ANID Basal Programme No. ACE210009 and FB210008 to PVB and AS; National Ph.D Fellowship by Agencia Nacional de Investigación (ANID) No. 21212138 to NA; ANID Associative Investigation Programme (PIA) No. ACT172066 to EM and PVB.

Publisher Copyright:
© 2022

ASJC Scopus subject areas

  • Cell Biology


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