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J. Biol. Chem., Vol. 280, Issue 10, 9728-9734, March 11, 2005

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GPI7 Is the Second Partner of PIG-F and Involved in Modification of Glycosylphosphatidylinositol^*

Nobue Shishioh, Yeongjin Hong¶||, Kazuhito Ohishi, Hisashi Ashida, Yusuke Maeda, and Taroh Kinoshita**

From the Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan, ^¶Department of Microbiology, Genomic Research Center for Enteropathogenic Bacteria, Chonnam National University Medical School, Gwangju 501-746, Korea, and ^**Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan

Many eukaryotic cell surface proteins are anchored to the membrane via glycosylphosphatidylinositol (GPI). GPI is synthesized from phosphatidylinositol by stepwise reactions and attached en bloc to nascent proteins. In mammalian cells, the major GPI species transferred to proteins is termed H7. By attachment of an additional ethanolamine phosphate (EtNP) to the second mannose, H7 can be converted to H8, which acts as a minor type of protein-linked GPI and also exists as a free GPI on the cell surface. Yeast GPI7 is involved in the transfer of EtNP to the second mannose, but the corresponding mammalian enzyme has not yet been clarified. Here, we report that the human homolog of Gpi7p (hGPI7) forms a protein complex with PIG-F and is involved in the H7-to-H8 conversion. We knocked down hGPI7 by RNA interference and found that H7 accumulated with little production of H8. Immunoprecipitation experiments revealed that hGPI7 was associated with and stabilized by PIG-F, which is known to bind to and stabilize PIG-O, a protein homologous to hGPI7. PIG-O is a transferase that adds EtNP to the third mannose, rendering GPI capable of attaching to proteins. We further found that the overexpression of hGPI7 decreased the level of PIG-O and, therefore, decreased the level of EtNP transferred to the third mannose. Finally, we propose a mechanism for the regulation of GPI biosynthesis through competition between the two independent enzymes, PIG-O and hGPI7, for the common stabilizer, PIG-F.

Received for publication, December 7, 2004 , and in revised form, December 29, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) NM_017733.

^* This work was supported in part by grants from the Ministry of Education, Science, Sports, Culture 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.

Both authors contributed equally to this work.

^|| Supported in part by Ministry of Health and Welfare, Korea, Grant 01-PJ10-PG6-01GM-02-002 and Korea Research Foundation Grant KRF-2004-003-E00019.

To whom correspondence should be addressed: Dept. of Immunoregulation, Research Institute for Microbial Diseases, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-8328; Fax: 81-6-6875-5233; E-mail: tkinoshi{at}biken.osaka-u.ac.jp.

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