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J. Biol. Chem., Vol. 280, Issue 44, 36674-36682, November 4, 2005

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Regulation of the Sphingoid Long-chain Base Kinase Lcb4p by Ergosterol and Heme

STUDIES IN PHYTOSPHINGOSINE-RESISTANT MUTANTS^*

From the Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-choume, Kita-ku, Sapporo 060-0812, Japan

Sphingoid long-chain base 1-phosphates (LCBPs) are widely conserved, bioactive lipid molecules. In yeast, LCBPs are known to be involved in several cellular responses such as heat shock resistance and Ca²⁺ mobilization, although their target molecules and signaling pathways remain unclear. To identify genes involved in LCBP signaling and in regulation of LCBP synthesis, we performed transposon mutagenesis in cells lacking the LCBP lyase DPL1 and LCBP phosphatase LCB3 genes and screened for phytosphingosine-resistant clones. Further isolation and identification revealed eight genes (PBP1, HEM14, UFD4, HMG1, TPS1, KES1, WHI2, and ERG5), in addition to the previously characterized LCB4 and PDR5 genes, that are involved in phytosphingosine resistance. Of these eight, four are ergosterol-related genes (HEM14, HMG1, KES1, and ERG5). We also demonstrated that protein expression of the long-chain base kinase Lcb4p was reduced in hem14 and hmg1 cells, likely as a consequence of decreased activity of the heme-dependent transcription factor Hap1p. In addition, phosphorylation of Lcb4p was decreased in all the ergosterol-related mutants isolated and other ergosterol mutants constructed (erg2, erg3, and erg6). Finally, plasma membrane localization of Lcb4p was found to be reduced in erg6 cells. These results suggest that changes in sterol composition affect the phosphorylation of Lcb4p because of the altered localization. The other genes isolated (PBP1, UFD4, TPS1, and WHI2) may be involved in LCBP signaling.

Received for publication, March 22, 2005 , and in revised form, August 31, 2005.

^* This work was supported by Grant-in-aid for Young Scientists (A) 17687011 from the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan. 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. Tel.: 81-11-706-3971; Fax: 81-11-706-4986; E-mail: kihara{at}pharm.hokudai.ac.jp.

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				S. Iwaki, T. Sano, T. Takagi, M. Osumi, A. Kihara, and Y. Igarashi Intracellular Trafficking Pathway of Yeast Long-chain Base Kinase Lcb4, from Its Synthesis to Its Degradation J. Biol. Chem., September 28, 2007; 282(39): 28485 - 28492. [Abstract] [Full Text] [PDF]