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J. Biol. Chem., Vol. 281, Issue 18, 12618-12624, May 5, 2006

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The Ubiquitin Isopeptidase UBPY Regulates Endosomal Ubiquitin Dynamics and Is Essential for Receptor Down-regulation^*

From the Physiological Laboratory, University of Liverpool, Crown Street, L69 3BX Liverpool, United Kingdom

UBPY is a ubiquitin-specific protease that can deubiquitinate monoubiquitinated receptor tyrosine kinases, as well as process Lys-48- and Lys-63-linked polyubiquitin to lower denomination forms in vitro. Catalytically inactive UBPY localizes to endosomes, which accumulate ubiquitinated proteins. We have explored the sequelae of short interfering RNA-mediated knockdown of UBPY. Global levels of ubiquitinated protein increase and ubiquitin accumulates on endosomes, although free ubiquitin levels are unchanged. UBPY-depleted cells have more and larger multivesicular endosomal structures that are frequently associated through extended contact areas, characterized by regularly spaced, electron-dense, bridging profiles. Degradation of acutely stimulated receptor tyrosine kinases, epidermal growth factor receptor and Met, is strongly inhibited in UBPY knockdown cells suggesting that UBPY function is essential for growth factor receptor down-regulation. In contrast, stability of the UBPY binding partner STAM is dramatically compromised in UBPY knockdown cells. The cellular functions of UBPY are complex but clearly distinct from those of the Lys-63-ubiquitin-specific protease, AMSH, with which it shares a binding site on the SH3 domain of STAM.

Received for publication, November 28, 2005 , and in revised form, February 22, 2006.

^* This work was supported by a Wellcome Trust Career Development Award (to S. U.). 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 A Royal Society University Fellow.

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

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