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Vol. 19, Issue 3, 1252-1260, March 2008

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The Ubiquitin-like Protein PLIC-2 Is a Negative Regulator of G Protein-coupled Receptor Endocytosis

Elsa-Noah N'Diaye^*,, Aylin C. Hanyaloglu^,, Kimberly K. Kajihara, Manojkumar A. Puthenveedu^||, Ping Wu^¶, Mark von Zastrow^||, and Eric J. Brown

*Macrophage Biology Laboratory, Veterans Affairs Medical Center, San Francisco, CA 94121; Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom; Department of Microbial Pathogenesis, Genentech, Inc., San Francisco, CA 94080; ^||Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94158-2517; and ^¶Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143-0451

Submitted August 13, 2007; Revised December 20, 2007; Accepted January 4, 2008
Monitoring Editor: Sandra Schmid

The activity of many signaling receptors is regulated by their endocytosis via clathrin-coated pits (CCPs). For G protein-coupled receptors (GPCRs), recruitment of the adaptor protein arrestin to activated receptors is thought to be sufficient to drive GPCR clustering in CCPs and subsequent endocytosis. We have identified an unprecedented role for the ubiquitin-like protein PLIC-2 as a negative regulator of GPCR endocytosis. Protein Linking IAP to Cytoskeleton (PLIC)-2 overexpression delayed ligand-induced endocytosis of two GPCRs: the V2 vasopressin receptor and β-2 adrenergic receptor, without affecting endocytosis of the transferrin or epidermal growth factor receptor. The closely related isoform PLIC-1 did not affect receptor endocytosis. PLIC-2 specifically inhibited GPCR concentration in CCPs, without affecting membrane recruitment of arrestin-3 to activated receptors or its cellular levels. Depletion of cellular PLIC-2 accelerated GPCR endocytosis, confirming its regulatory function at endogenous levels. The ubiquitin-like domain of PLIC-2, a ligand for ubiquitin-interacting motifs (UIMs), was required for endocytic inhibition. Interestingly, the UIM-containing endocytic adaptors epidermal growth factor receptor protein substrate 15 and Epsin exhibited preferential binding to PLIC-2 over PLIC-1. This differential interaction may underlie PLIC-2 specific effect on GPCR endocytosis. Identification of a negative regulator of GPCR clustering reveals a new function of ubiquitin-like proteins and highlights a cellular requirement for exquisite regulation of receptor dynamics.

These authors contributed equally to this work.

Address correspondence to: Eric Joel Brown (ericbr{at}gene.com)

Abbreviations used: β2AR, β2-adrenergic receptor; CCP, clathrin-coated pit; EGFR, epidermal growth factor receptor; Eps15, epidermal growth factor receptor protein substrate 15; PLIC, protein linking IAP to cytoskeleton; TfR, transferrin receptor; UBA, ubiquitin-associated-; UbL, ubiquitin-like; UIM, ubiquitin-interacting motif; V2R, V2 vasopressin receptor.

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