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J. Biol. Chem., Vol. 282, Issue 48, 34770-34778, November 30, 2007

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The Cyclophilin-like Domain of Ran-binding Protein-2 Modulates Selectively the Activity of the Ubiquitin-Proteasome System and Protein Biogenesis^*

Haiqing Yi, Julie L. Friedman, and Paulo A. Ferreira¹

From the Departments of Ophthalmology and Molecular Genetics and Microbiology, Duke University, Medical Center, Durham, North Carolina 27710

The ubiquitin-proteasome system (UPS) plays a critical role in protein degradation. The 19S regulatory particle (RP) of the 26S proteasome mediates the recognition, deubiquitylation, unfolding, and channeling of ubiquitylated substrates to the 20S proteasome. Several subunits of the 19S RP interact with a growing number of factors. The cyclophilin-like domain (CLD) of Ran-binding protein-2 (RanBP2/Nup358) associates specifically with at least one subunit, S1, of the base subcomplex of the 19S RP, but the functional implications of this interaction on the UPS activity are elusive. This study shows the CLD of RanBP2 promotes selectively the accumulation of a subset of reporter substrates of the UPS, such as the ubiquitin (Ub)-fusion yellow fluorescent protein (YFP) degradation substrate, Ub^G76V-YFP, and the N-end rule substrate, Ub-R-YFP. Conversely, the degradation of endoplasmic reticulum and misfolded proteins, and of those linked to UPS-independent degradation, is not affected by CLD. The selective effect of CLD on the UPS in vivo is independent of, and synergistic with, proteasome inhibitors, and CLD does not affect the intrinsic proteolytic activity of the 20S proteasome. The inhibitory activity of CLD on the UPS resides in a purported SUMO binding motif. We also found two RanBP2 substrates, RanGTPase-activating protein and retinitis pigmentosa GTPase regulator interacting protein-11, whose steady-state levels are selectively modulated by CLD. Hence, the CLD of RanBP2 acts as a novel auxiliary modulator of the UPS activity; it may contribute to the molecular and subcellular compartmentation of the turnover of properly folded proteins and modulation of the expressivity of several neurological diseases.

Received for publication, August 17, 2007 , and in revised form, October 1, 2007.

^* This work was supported in part by National Institutes of Health Grants EY011993 (to P. A. F.) and 2P30-EY005722-21. 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 Jules & Doris Stein Research to Prevent Blindness Professor. To whom correspondence should be addressed: Depts. of Ophthalmology and Molecular Genetics and Microbiology, Duke University Medical Center, DUEC 3802, Erwin Road, Durham, NC 27710. Tel.: 919-684-8457; Fax: 919-684-6545; E-mail: ferre044{at}mc.duke.edu.

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