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Vol. 20, Issue 13, 3088-3100, July 1, 2009

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The Cytoplasmic Tail of GM3 Synthase Defines Its Subcellular Localization, Stability, and In Vivo Activity

Satoshi Uemura^*, Sayaka Yoshida^*, Fumi Shishido^*, and Jin-ichi Inokuchi^*,

*Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi 981-8558, Japan; and Core Research for Evolutional Science and Technology Program (CREST), Japan Science and Technology Agency (JST), Saitama, 332-0012, Japan

Submitted December 17, 2008; Revised April 8, 2009; Accepted April 29, 2009
Monitoring Editor: Benjamin S. Glick

GM3 synthase (SAT-I) is the primary glycosyltransferase responsible for the biosynthesis of ganglio-series gangliosides. In this study, we identify three isoforms of mouse SAT-I proteins, named M1-SAT-I, M2-SAT-I, and M3-SAT-I, which possess distinct lengths in their NH₂-terminal cytoplasmic tails. These isoforms are produced by leaky scanning from mRNA variants of mSAT-Ia and mSAT-Ib. M2-SAT-I and M3-SAT-I were found to be localized in the Golgi apparatus, as expected, whereas M1-SAT-I was exclusively found in the endoplasmic reticulum (ER). Specific multiple arginines (R) arranged in an R-based motif, RRXXXXR necessary for ER targeting, were found in the cytoplasmic tail of M1-SAT-I, and in vivo GM3 biosynthesis by M1-SAT-I was very low because of restricted transport to the Golgi apparatus. In addition, M1-SAT-I and M3-SAT-I had a long half-life relative to M2-SAT-I. This is the first report demonstrating the presence of an ER-targeting R-based motif in the cytoplasmic tail of a protein in the mammalian glycosyltransferase family of enzymes. The system, which produces SAT-I isoforms having distinct characteristics, is likely to be of critical importance for the regulation of GM3 biosynthesis under various pathological and physiological conditions.

Address correspondence to: Jin-ichi Inokuchi (jin{at}tohoku-pharm.ac.jp).

Abbreviations used: aa, amino acid residues; CHO, Chinese hamster ovary; Cys, cysteine; EGFP, enhanced green fluorescent protein; ER, endoplasmic reticulum; Endo H, endoglycosidase H; ks, kozak sequence; LacCer, lactosylceramide; Met, methionine; PNGase F, peptide: N-glycosidase F; 5'-UTR, 5'-untranslated region.

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