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J. Biol. Chem., Vol. 282, Issue 42, 30929-30937, October 19, 2007

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The MIT Domain of UBPY Constitutes a CHMP Binding and Endosomal Localization Signal Required for Efficient Epidermal Growth Factor Receptor Degradation^*

Paula E. Row, Han Liu, Sebastian Hayes¹, Rebecca Welchman, Panagoula Charalabous, Kay Hofmann, Michael J. Clague, Christopher M. Sanderson, and Sylvie Urbé²

From the Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Crown Street, LiverpoolL693BX, United Kingdom and The Bioinformatics Group, Miltenyi Biotec GmbH, Stoeckheimer Weg 1, 50829 Koeln, Germany

We have identified and characterized a Microtubule Interacting and Transport (MIT) domain at the N terminus of the deubiquitinating enzyme UBPY/USP8. In common with other MIT-containing proteins such as AMSH and VPS4, UBPY can interact with CHMP proteins, which are known to regulate endosomal sorting of ubiquitinated receptors. Comparison of binding preferences for the 11 members of the human CHMP family between the UBPY MIT domain and another ubiquitin isopeptidase, AMSH, reveals common interactions with CHMP1A and CHMP1B but a distinct selectivity of AMSH for CHMP3/VPS24, a core subunit of the ESCRT-III complex, and UBPY for CHMP7. We also show that in common with AMSH, UBPY deubiquitinating enzyme activity can be stimulated by STAM but is unresponsive to its cognate CHMPs. The UBPY MIT domain is dispensable for its catalytic activity but is essential for its localization to endosomes. This is functionally significant as an MIT-deleted UBPY mutant is unable to rescue its binding partner STAM from proteasomal degradation or reverse a block to epidermal growth factor receptor degradation imposed by small interfering RNA-mediated depletion of UBPY.

Received for publication, May 15, 2007 , and in revised form, August 6, 2007.

^* This work was supported in part by the Wellcome Trust, North West Cancer Research Fund, and Cancer Research UK (CRUK). 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 Recipient of a Wellcome Trust studentship.

² A CRUK Senior Research Fellow. To whom correspondence should be addressed. Tel.: 49-151-794-5432; Fax: 44-151-794-4434; E-mail: urbe{at}liv.ac.uk.

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