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Vol. 20, Issue 12, 2979-2990, June 15, 2009

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Normal Formation of a Subset of Intestinal Granules in Caenorhabditis elegans Requires ATP-binding Cassette Transporters HAF-4 and HAF-9, Which Are Highly Homologous to Human Lysosomal Peptide Transporter TAP-Like

Hiromi Kawai^*,, Takahiro Tanji^,, Hirohisa Shiraishi^,, Mitsuo Yamada^*, Ryoko Iijima^*, Takao Inoue, Yasuko Kezuka^*, Kazuaki Ohashi^*, Yasuo Yoshida^||, Koujiro Tohyama^||, Keiko Gengyo-Ando^¶, Shohei Mitani^¶, Hiroyuki Arai, Ayako Ohashi-Kobayashi^*,, and Masatomo Maeda^*,#

*Department of Molecular Biology and Biochemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan; Department of Immunobiology, School of Pharmacy, Iwate Medical University, Yahaba, Shiwa-gun, Iwate 028-3694, Japan; Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; ^||The Center for Electron Microscopy and Bio-Imaging Research, Iwate Medical University, Morioka, Iwate 020-8505, Japan; and ^¶Department of Physiology, School of Medicine, Tokyo Women's Medical University, Shinjuku-ku, Tokyo 162-8666, Japan

Submitted September 8, 2008; Revised April 10, 2009; Accepted April 17, 2009
Monitoring Editor: Thomas F.J. Martin

TAP-like (TAPL; ABCB9) is a half-type ATP-binding cassette (ABC) transporter that localizes in lysosome and putatively conveys peptides from cytosol to lysosome. However, the physiological role of this transporter remains to be elucidated. Comparison of genome databases reveals that TAPL is conserved in various species from a simple model organism, Caenorhabditis elegans, to mammals. C. elegans possesses homologous TAPL genes: haf-4 and haf-9. In this study, we examined the tissue-specific expression of these two genes and analyzed the phenotypes of the loss-of-function mutants for haf-4 and haf-9 to elucidate the in vivo function of these genes. Both HAF-4 and HAF-9 tagged with green fluorescent protein (GFP) were mainly localized on the membrane of nonacidic but lysosome-associated membrane protein homologue (LMP-1)-positive intestinal granules from larval to adult stage. The mutants for haf-4 and haf-9 exhibited granular defects in late larval and young adult intestinal cells, associated with decreased brood size, prolonged defecation cycle, and slow growth. The intestinal granular phenotype was rescued by the overexpression of the GFP-tagged wild-type protein, but not by the ATP-unbound form of HAF-4. These results demonstrate that two ABC transporters, HAF-4 and HAF-9, are related to intestinal granular formation and some other physiological aspects.

These authors contributed equally to this work.

^# Present address: Department of Molecular Biology, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Shiwa-gun, Iwate 028-3694, Japan.

Address correspondence to: Ayako Ohashi-Kobayashi (aohashi{at}iwate-med.ac.jp)

Abbreviations used: ABC, ATP-binding cassette; DIC, differential interference contrast; DMSO, dimethyl sulfoxide; GFP, green fluorescent protein; LAMP, lysosome-associated membrane protein; mRFP, monomeric red fluorescent protein; MRP, multidrug resistance-associated protein; PBS, phosphate-buffered saline; PBS-T, PBS containing 0.1%, wt/wt, Tween-20; TAP, transporter associated with antigen processing; TAPL, TAP-like.

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