The proteasome maturation factor POMP moonlights as a stress-induced transcriptional regulator

Giandomenico, S. L.; Mueller, M.; van Oostrum, M.; Desch, K.; Krause, B.; Tushev, G.; Ciirdaeva, E.; Langer, J. D.; Alvarez-Castelao, B.; Schuman, E. M.

doi:10.1101/2025.04.25.650603

bioRxiv · 10.1101/2025.04.25.650603

The proteasome maturation factor POMP moonlights as a stress-induced transcriptional regulator

Giandomenico, S. L.·Mueller, M.·van Oostrum, M.·Desch, K.·Krause, B.·Tushev, G.·Ciirdaeva, E.·Langer, J. D.·Alvarez-Castelao, B.·Schuman, E. M.

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Abstract

Proteostasis - the maintenance of proteins at proper concentrations, conformations, and subcellular locations - is essential for cellular function and is governed by tightly regulated protein synthesis and degradation pathways. The Proteasome Maturation Protein (POMP) is a key chaperone involved in assembling the proteasome, the primary complex responsible for protein degradation. Despite the conserved role of POMP, its loss produces contrasting proteostatic effects in yeast and mammalian cells, pointing to additional, unexplored functions. In this study, we investigated the possibility that POMP plays a moonlighting role in proteostasis regulation. We discovered that upon proteasome disruption, POMP rapidly accumulates in the nucleolus in a manner dependent on HSF1 and reactive oxygen species (ROS). Proteomic analysis of POMP interactors revealed RNA processing factors and transcriptomic profiling showed that nucleolar POMP orchestrates a protective transcriptional program. Our findings indicate POMP is a built-in sensor and effector within the proteasome assembly pathway, capable of buffering disturbances in proteasome function through a novel, non-canonical role. Notably, this mechanism is developmentally controlled and active in neurodegenerative disease contexts. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/650603v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@196cd2borg.highwire.dtl.DTLVardef@177d240org.highwire.dtl.DTLVardef@18c9bcborg.highwire.dtl.DTLVardef@483b94_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Giandomenico, S. L., Mueller, M., van Oostrum, M., Desch, K., Krause, B., Tushev, G., Ciirdaeva, E., Langer, J. D., Alvarez-Castelao, B., Schuman, E. M.. 2025-04-27. The proteasome maturation factor POMP moonlights as a stress-induced transcriptional regulator. https://doi.org/10.1101/2025.04.25.650603

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