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Vol. 20, Issue 11, 2639-2649, June 1, 2009

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Identification of the Neuroblastoma-amplified Gene Product as a Component of the Syntaxin 18 Complex Implicated in Golgi-to-Endoplasmic Reticulum Retrograde Transport

Takehiro Aoki^*,, Sarah Ichimura^*,, Ayano Itoh^*, Mami Kuramoto^*, Takashi Shinkawa, Toshiaki Isobe, and Mitsuo Tagaya^*

*School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan; and Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan

Submitted November 10, 2008; Revised March 26, 2009; Accepted April 2, 2009
Monitoring Editor: Vivek Malhotra

Syntaxin 18, a soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) protein implicated in endoplasmic reticulum (ER) membrane fusion, forms a complex with other SNAREs (BNIP1, p31, and Sec22b) and several peripheral membrane components (Sly1, ZW10, and RINT-1). In the present study, we showed that a peripheral membrane protein encoded by the neuroblastoma-amplified gene (NAG) is a subunit of the syntaxin 18 complex. NAG encodes a protein of 2371 amino acids, which exhibits weak similarity to yeast Dsl3p/Sec39p, an 82-kDa component of the complex containing the yeast syntaxin 18 orthologue Ufe1p. Under conditions favoring SNARE complex disassembly, NAG was released from syntaxin 18 but remained in a p31-ZW10-RINT-1 subcomplex. Binding studies showed that the extreme N-terminal region of p31 is responsible for the interaction with NAG and that the N- and the C-terminal regions of NAG interact with p31 and ZW10-RINT-1, respectively. Knockdown of NAG resulted in a reduction in the expression of p31, confirming their intimate relationship. NAG depletion did not substantially affect Golgi morphology and protein export from the ER, but it caused redistribution of Golgi recycling proteins accompanied by a defect in protein glycosylation. These results together suggest that NAG links between p31 and ZW10-RINT-1 and is involved in Golgi-to-ER transport.

These authors contributed equally to this work.

Address correspondence to: Mitsuo Tagaya (tagaya{at}ls.toyaku.ac.jp)

Abbreviations used: ER, endoplasmic reticulum; ERGIC, ER-Golgi intermediate compartment; GFP, green fluorescent protein; KDEL-R, KDEL receptor; mAb, monoclonal antibody; Man II, mannosidase II; NAG, neuroblastoma-amplified gene; PNGase F, peptide:N-glycosidase F; siRNA, short interfering RNA; SNARE, N-ethylmaleimide-sensitive factor attachment protein receptor; TMD, transmembrane domain; VSVG, vesicular stomatitis virus-encoded glycoprotein; YFP, yellow fluorescent protein.

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