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FAM134B clustering by liquid-like condensates facilitates RhoA sequestration and cell morphology

ABSTRACT: The extensive cytoplasmic regions of ER-phagy receptors suggest integration of ER remodelling with cytoplasmic changes. Here, we present a cytoplasmic interactome of prominent receptors. Within this, regulatory interactors of FAM134B/C are identified by targeted CRISPR/Cas9 screening. We identify PRKAR1A as a direct activator of FAM134B/C, binding through an amphipathic helix within the otherwise disordered C-terminal region of FAM134B. Super-resolution, FRAP and CLEM imaging demonstrate that irregular, liquid-like condensates of cAMP-bound PRKAR1A form ER contacts, promoting clustering of FAM134B with LC3B. Proximity proteomics reveal that cAMP induces FAM134B interaction with cytoplasmic RhoA, co-degradation within condensate-associated lysosomes, and reduction in peripheral actomyosin contractility. Physiologically, co-ordination of ER and cytoplasmic remodelling is required for canonical cAMP-regulated cell morphologic changes, including determination of the matrix invasion modality of cancer cells. In summary, bidirectional cross-talk between the ER and the cytoplasm is facilitated by FAM134B/C and cytoplasmic liquid condensates.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Alex von Kriegsheim

LAB HEAD: ALex von Kriegsheim

PROVIDER: PXD069063 | Pride | 2026-06-17

REPOSITORIES: Pride

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			Action	DRS
	20250221_Natalia.zip	Other
	Apriltxt.zip	Other
	CCPG1-1.raw	Raw
	CCPG1-2.raw	Raw
	CCPG1-3.raw	Raw

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