title: Regulation of endocytic clathrin dynamics by cargo ubiquitination.
abstract: Some endocytic cargoes control clathrin-coated pit (CCP) maturation, but it is not known how such regulation is communicated. We found that μ-opioid neuropeptide receptors signal to their enclosing CCPs by ubiquitination. Nonubiquitinated receptors delay CCPs at an intermediate stage of maturation, after clathrin lattice assembly is complete but before membrane scission. Receptor ubiquitination relieves this inhibition, effectively triggering CCP scission and producing a receptor-containing endocytic vesicle. The ubiquitin modification that conveys this endocytosis-promoting signal is added to the receptor's first cytoplasmic loop, catalyzed by the Smurf2 ubiquitin ligase, and coordinated with activation-dependent receptor phosphorylation and clustering through Smurf2 recruitment by the endocytic adaptor beta-arrestin. Epsin1 detects the signal at the CCP and is required for ubiquitin-promoted scission. This cargo-to-coat communication system mediates a biochemical checkpoint that ensures appropriate receptor ubiquitination for later trafficking, and it controls specific receptor loading into CCPs by sensing when a sufficient quorum is reached.
authors.affiliation: Program in Cell Biology, Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Anastasia G
authors.initials: AG
authors.lastname: Henry
authors.forename: James N
authors.initials: JN
authors.lastname: Hislop
authors.forename: Joe
authors.initials: J
authors.lastname: Grove
authors.forename: Kurt
authors.initials: K
authors.lastname: Thorn
authors.forename: Mark
authors.initials: M
authors.lastname: Marsh
authors.forename: Mark
authors.initials: M
authors.lastname: von Zastrow
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism*; D003034:Coated Pits, Cell-Membrane / Q000378:metabolism*; D004705:Endocytosis; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D017450:Receptors, Opioid, mu / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002966:Clathrin; D017450:Receptors, Opioid, mu; D025801:Ubiquitin; C114154:epsin; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases