DYRK3 enables secretory trafficking by maintaining the liquid-like state of ER exit sites

Raffaella Gallo; Arpan Kumar Rai; Alexa B R McIntyre; Katrina Meyer; Lucas Pelkmans

doi:10.1016/j.devcel.2023.08.005

DYRK3 enables secretory trafficking by maintaining the liquid-like state of ER exit sites

Dev Cell. 2023 Oct 9;58(19):1880-1897.e11. doi: 10.1016/j.devcel.2023.08.005. Epub 2023 Aug 28.

Authors

Raffaella Gallo¹, Arpan Kumar Rai², Alexa B R McIntyre¹, Katrina Meyer¹, Lucas Pelkmans³

Affiliations

¹ Department of Molecular Life Sciences, University of Zurich, 8046 Zurich, Switzerland.
² Department of Molecular Life Sciences, University of Zurich, 8046 Zurich, Switzerland. Electronic address: arpan.rai@mls.uzh.ch.
³ Department of Molecular Life Sciences, University of Zurich, 8046 Zurich, Switzerland. Electronic address: lucas.pelkmans@mls.uzh.ch.

PMID: 37643612
DOI: 10.1016/j.devcel.2023.08.005

Abstract

The dual-specificity kinase DYRK3 controls the formation and dissolution of multiple biomolecular condensates, regulating processes including stress recovery and mitotic progression. Here, we report that DYRK3 functionally interacts with proteins associated with endoplasmic reticulum (ER) exit sites (ERESs) and that inhibition of DYRK3 perturbs the organization of the ERES-Golgi interface and secretory trafficking. DYRK3-mediated regulation of ERES depends on the N-terminal intrinsically disordered region (IDR) of the peripheral membrane protein SEC16A, which co-phase separates with ERES components to form liquid-like condensates on the surface of the ER. By modulating the liquid-like properties of ERES, we show that their physical state is essential for functional cargo trafficking through the early secretory pathway. Our findings support a mechanism whereby phosphorylation by DYRK3 and its reversal by serine-threonine phosphatases regulate the material properties of ERES to create a favorable physicochemical environment for directional membrane traffic in eukaryotic cells.

Keywords: COPII; DYRK3; ERES; LLPS; SEC16A; kinase; material properties; optogenetics; phase separation; secretory pathway.