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J. Biol. Chem., Vol. 283, Issue 33, 22774-22786, August 15, 2008

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Scyl1, Mutated in a Recessive Form of Spinocerebellar Neurodegeneration, Regulates COPI-mediated Retrograde Traffic^*

Jonathon L. Burman¹, Lyne Bourbonniere, Jacynthe Philie, Thomas Stroh¹, Selma Y. Dejgaard, John F. Presley, and Peter S. McPherson²

From the Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada and the Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 2B2, Canada

Scy1-like 1 (Scyl1), a member of the Scy1-like family of catalytically inactive protein kinases, was recently identified as the gene product altered in muscle-deficient mice, which suffer from motor neuron degeneration and cerebellar atrophy. To determine the function of Scyl1, we have now used a mass spectrometry-based screen to search for Scyl1-binding partners and identified components of coatomer I (COPI) coats. The interaction was confirmed in pull-down assays, and Scyl1 co-immunoprecipitates with βCOP from brain lysates. Interestingly, and unique for a non-transmembrane domain protein, Scyl1 binds COPI coats using a C-terminal RKLD-COO^- sequence, similar to the KKXX-COO^- COPI-binding motif found in transmembrane endoplasmic reticulum (ER) proteins. Scyl1 co-localizes with βCOP and is localized, in an Arf1-independent manner, to the ER-Golgi intermediate compartment and the cis-Golgi, sites of COPI-mediated membrane budding. The localization and binding properties of Scyl1 strongly suggest a function in COPI transport, and inhibitory RNA-mediated knock down of the protein disrupts COPI-mediated retrograde traffic of the KDEL receptor to the ER without affecting anterograde traffic from the ER. Our data demonstrate a function for Scyl1 as an accessory factor in COPI trafficking and suggest for the first time that alterations in the COPI pathway result in neurodegenerative disease.

Received for publication, March 7, 2008 , and in revised form, June 5, 2008.

^* This work was supported by Grant MOP-13461 from the Canadian Institutes of Health Research (CIHR) (to P. S. M.) and by a grant from the Great-West Life, London Life and Canada Life Experimental Therapeutics Fund at the Montreal Neurological Institute. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures and five supplemental figures.

This article was selected as a Paper of the Week.

¹ A recipient of a CIHR Canada Graduate Scholarships Award.

² A Fonds de la recherché en santé du Québec Senior Scholar and holds the James McGill Chair. To whom correspondence should be addressed: Dept. of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University, Montreal, QC, Canada, H3A 2B4. Tel.: 514-398-7355; Fax: 514-398-8106; E-mail: peter.mcpherson{at}mcgill.ca.

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