HRS dephosphorylation at membrane contact sites promotes sorting within multivesicular endosomes.

Rapid dephosphorylation of HRS at ER:MVE membrane contact sites promotes efficient EGF-stimulated ILV formation, and this effect depends on HRS Y329/334 phosphorylation status.

• Why it matters: HRS helps sort ubiquitylated cargo into MVEs for lysosomal degradation, but how its phosphorylation is regulated at membrane contact sites to control ILV formation is unclear.
• What they did: They co-depleted STAM1 and STAM2 to model EGFR sorting defects, then used endogenous HRS mutagenesis and APEX2-tagged HRS variants to test whether HRS Y329/334 phosphorylation controls EGFR sorting and MVE size.
• The result: AnnexinA1-mediated ER:endosomal contacts increased ILV formation, while AnnexinA1 depletion increased HRS phosphorylation, likely via reduced ER-localized PTP1B dephosphorylation; the Y329/334 mutation made ILV formation insensitive to AnnexinA1 loss.

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