Regulation of Endocytic Clathrin Dynamics by Cargo Ubiquitination

• Published in: Developmental cell Vol. 23; no. 3; pp. 519 - 532
• Main Authors: Henry, Anastasia G., Hislop, James N., Grove, Joe, Thorn, Kurt, Marsh, Mark, von Zastrow, Mark
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 11-09-2012; Cell Press
• Subjects: Adaptor Proteins, Vesicular Transport - metabolism; Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Clathrin - metabolism; Coated Pits, Cell-Membrane - metabolism; Endocytosis; Fundamental and applied biological sciences. Psychology; HEK293 Cells; Humans; Molecular and cellular biology; Phosphorylation; Receptors, Opioid, mu - metabolism; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Development; Clathrin; Endocytosis; Regulation(control)
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2012.08.003

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.
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► μ-opioid receptor (MOR) ubiquitination by the E3 ligase Smurf2 triggers endocytosis ► Nonubiquitinated MORs prolong the surface lifetime of clathrin-coated pits (CCPs) ► Kinetic control of CCPs assures receptor ubiquitination for postendocytic traffic ► Kinetic control of CCPs also helps determine endocytic cargo load
Some endocytic cargoes regulate clathrin-coated pit (CCP) maturation, but how such regulation is communicated remains unknown. Henry et al. show that μ-opioid receptors signal to their enclosing CCPs by ubiquitination, allowing cargo-mediated control of CCP dynamics. The authors suggest that this modulates the receptor load of CCPs and, later, receptor trafficking.