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bioRxiv · 10.64898/2026.02.04.703745

PERK retains a predominantly monomeric state under ER stress conditions

Georgoula, K.·Liu, L.·Jung, S.·Sohail, I.·Annibale, P.·Schiattarella, G.
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Abstract

The unfolded protein response (UPR) is a central adaptive mechanism that safeguards protein homeostasis in the endoplasmic reticulum (ER). In the heart, UPR signaling contributes to cellular remodeling and survival across a range of pathological contexts, including ischemia, pressure overload, and cardiometabolic stress. Among the three canonical UPR branches, the PKR-like ER kinase (PERK) pathway plays a critical role in modulating translational control and redox balance during stress adaptation. Despite its functional importance, the molecular dynamics of PERK activation and assembly remain incompletely understood. Here, we investigate the oligomerization behavior of PERK in living cells using advanced fluorescence microscopy. We identify a concentration-dependent mechanism of PERK self-association, as well as a distinct population of oligomeric PERK whose assembly state remains stable upon ER stress induction. These findings challenge the traditional view of stress-induced oligomerization as a prerequisite for PERK activation and suggest the existence of non-canonical modes of PERK assembly with potential regulatory significance.

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Georgoula, K., Liu, L., Jung, S., Sohail, I., Annibale, P., Schiattarella, G.. 2026-02-06. PERK retains a predominantly monomeric state under ER stress conditions. https://doi.org/10.64898/2026.02.04.703745

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