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J. Biol. Chem., Vol. 281, Issue 8, 5094-5105, February 24, 2006

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Degradation of Endocytosed Epidermal Growth Factor and Virally Ubiquitinated Major Histocompatibility Complex Class I Is Independent of Mammalian ESCRTII^*

Katherine Bowers¹, Siân C. Piper, Melissa A. Edeling, Sally R. Gray, David J. Owen, Paul J. Lehner, and J. Paul Luzio

From the Cambridge Institute for Medical Research, Departments of Clinical Biochemistry and Medicine, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, United Kingdom

Models for protein sorting at multivesicular bodies in the endocytic pathway of mammalian cells have relied largely on data obtained from yeast. These data suggest the essential role of four ESCRT complexes in multivesicular body protein sorting. However, the putative mammalian ESCRTII complex (hVps25p, hVps22p, and hVps36p) has no proven functional role in endosomal transport. We have characterized the human ESCRTII complex and investigated its function in endosomal trafficking. The human ESCRTII proteins interact with one another, with hVps20p (a component of ESCRTIII), and with their yeast homologues. Our interaction data from yeast two-hybrid studies along with experiments with purified proteins suggest an essential role for the N-terminal domain of hVps22p in the formation of a heterotetrameric ESCRTII complex. Although human ESCRTII is found in the cytoplasm and in the nucleus, it can be recruited to endosomes upon overexpression of dominant-negative hVps4Bp. Interestingly, we find that small interference RNA depletion of mammalian ESCRTII does not affect degradation of epidermal growth factor, a known cargo of the multivesicular body protein sorting pathway. We also show that depletion of the deubiquitinating enzymes AMSH (associated molecule with the SH3 domain of STAM (signal transducing adaptor molecule)) and UBPY (ubiquitin isopeptidase Y) have opposite effects on epidermal growth factor degradation, with UBPY depletion causing dramatic swelling of endosomes. Down-regulation of another cargo, the major histocompatibility complex class I in cells expressing the Kaposi sarcoma-associated herpesvirus protein K3, is unaffected in ESCRTII-depleted cells. Our data suggest that mammalian ESCRTII may be redundant, cargo-specific, or not required for protein sorting at the multivesicular body.

Received for publication, August 5, 2005 , and in revised form, November 28, 2005.

^* This work was supported by a British Heart Foundation Intermediate Fellowship (to K. B.), a Wellcome Trust studentship (to S. C. P.), a Wellcome Trust Senior Research Fellowship (to D. J. O.), a Wellcome Trust Senior Clinical Research Fellowship (to P. J. L.), and the Medical Research Council UK (Research Grant G9310915 to J. P. L.). The Cambridge Institute for Medical Research was supported by the Wellcome Trust (Strategic Initiative Grant 066438). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 44-1-223-336-782; Fax: 44-1-223-762-640; E-mail: kb123{at}cam.ac.uk.

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