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J. Biol. Chem., Vol. 282, Issue 3, 1670-1678, January 19, 2007

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A Role For Lte1p (a Low Temperature Essential Protein Involved in Mitosis) in Proprotein Processing in the Yeast Secretory Pathway^*

Xiang Zhao, Amy Y. Chang^¶, Akio Toh-e^||, and Peter Arvan¹

From the Division of Metabolism, Endocrinology & Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48109, the Sue Golding Graduate Division, Albert Einstein College of Medicine, Bronx, New York 10461, the ^¶Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, and the ^||Department of Biological Science, University of Tokyo, Hongo 7-3-1, Tokyo 113-0033, Japan

We previously identified six single gene disruptions in Saccharomyces cerevisiae that allow enhanced immunoreactive insulin secretion primarily because of defective Kex2p-mediated endoproteolytic processing. Five eis mutants disrupted established VPS (vacuolar protein sorting) genes, The sixth, LTE1, is a Low Temperature (<15 °C) Essential gene encoding a large protein with potential guanine nucleotide exchange (GEF) domains. Lte1p functions as a positive regulator of the mitotic GTPase Tem1p, and overexpression of Tem1p suppresses the low temperature mitotic defect of lte1. By sequence analysis, Tem1p has highest similarity to Vps21p (yeast homolog of mammalian Rab5). Unlike TEM1, LTE1 is not restricted to mitosis but is expressed throughout the cell cycle. Lte1p function in interphase cells is largely unknown. Here we confirm the eis phenotype of lte1 mutant cells and demonstrate a defect in proalpha factor processing that is rescued by expression of full-length Lte1p but not a C-terminally truncated Lte1p lacking its GEF homology domain. Neither overexpression of Tem1p nor 13 other structurally related GTPases can suppress the secretory proprotein processing defect. However, overexpression of Vps21p selectively restores proprotein processing in a manner dependent upon the active GTP-bound form of the GTPase. By contrast, a vps21 mutant produces a synthetic defect with lte1 in proprotein processing, as well as a synthetic growth defect. Together, the data underscore a link between the mitotic regulator, Lte1p, and protein processing and trafficking in the secretory/endosomal system.

Received for publication, November 10, 2006

^* This work was supported in part by National Institutes of Health Grant DK48280 with help from the Molecular Biology Core of the U-M Diabetes Research and Training Center (NIH DK20572). 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: Division of Metabolism, Endocrinology & Diabetes, 5560 MSRB2, University of Michigan, 1500 E. Medical Ctr Dr., Ann Arbor MI 48109. Tel.: 734-936-5505; Fax: 734-936-6684; E-mail: parvan{at}umich.edu.

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