Calcineurin B-mediated Ca2+ sensing translates stress signal intensity into the assembly of phase-separated condensates at PERK complexes.

Authors

Bairo, S. M., Fernandez, M., Quassollo, G., Pellegrini, A., de Battista, J. C., Asis, S., Martin, M. G., Holstein, D., Lechleiter, J. D., Gomez, G. E., Bisbal, M., Bollo, M.

Abstract

Endoplasmic reticulum (ER) stress activates protein kinase RNA-like ER kinase (PERK), which initially promotes adaptive responses but remains the only active UPR branch during prolonged stress, mediating both early cytoprotective and chronic pro-apoptotic signaling. Recently, we identified translocon-generated Ca 2+ microdomains that promote PERK phosphorylation during early UPR, revealing a mechanism by which local Ca 2+ signals regulate UPR activation. However, the molecular mechanism linking these Ca 2+ microdomains to PERK activation remains elusive. Previously, we showed that calcineurin (CN), a Ca 2+-dependent heterodimer composed of catalytic (CNA) and regulatory (CNB) subunits, exerts a non-canonical pro-survival function by promoting PERK autophosphorylation. Here, using super-resolution microscopy, CRISPR-Cas9 editing, in silico analyses, and optogenetic droplet assays, we identify CNB as a local Ca 2+ sensor that couples translocon-generated Ca 2+ signals to liquid condensate assembly, thereby promoting adaptive PERK phosphorylation. These findings establish CNB-mediated condensate assembly as a mechanism that translates local Ca 2+ signals into spatially organized early adaptive PERK signaling.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 05 Aug 2026.

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