Authors
Natalia Jimenez-Moreno, Arianna Karageorgiou, Katie Winnington-Ingram, Jimi Wills, Chinmayi Pednekar, Melina Overhoff, Katherine Paine, Matthew Pearson, Lukas Gerasimavicius, Ann Wheeler, Natalia L Kononenko, Joseph A Marsh, Paul Verkade, Alex von Kriegsheim, Jon D Lane, Simon Wilkinson
Published in
Molecular cell. Aug 17, 2026. Epub Aug 17, 2026.
Abstract
Endoplasmic reticulum (ER)-phagy receptors have elusive physiological functions beyond ER remodeling. To gain insight into these, we screen for cytoplasmic interactors of well-known receptors in mouse pancreatic ductal adenocarcinoma cells. Our data subsequently reveal a non-canonical action of PRKAR1A, a subunit of protein kinase A (PKA), in binding and activating FAM134B/C. At a molecular level, an amphipathic helix in the otherwise-disordered C terminus of FAM134B directly binds PRKAR1A dimers. Multimodal imaging reveals that this interaction occurs at interorganellar contact sites between the ER and liquid-like condensates of PRKAR1A. Mechanistically, ER-condensate contacts promote clustering of FAM134B/C with LC3B and recruit lysosomes, forming degradation hubs. Unexpectedly, these structures are found to control cytoplasmic signaling through FAM134B/C-mediated lysosomal sequestration of RhoA. Underscoring the physiologic relevance of this, these cytoplasmic-facing actions of FAM134B/C result in RhoA-dependent cell morphologic and migratory control in response to cyclic AMP (cAMP) stimuli. Thus, interorganellar contacts expand the roles of FAM134B/C ER-phagy receptors beyond ER degradation.
PMID:
42607684
Bibliographic data and abstract were imported from PubMed on 18 Aug 2026.
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