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J. Biol. Chem., Vol. 279, Issue 44, 46253-46262, October 29, 2004

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Human Acyl-Coenzyme A:Cholesterol Acyltransferase 1 (acat1) Sequences Located in Two Different Chromosomes (7 and 1) Are Required to Produce a Novel ACAT1 Isoenzyme with Additional Sequence at the N Terminus^*

Li Yang, Oneil Lee, Jia Chen, Jiang Chen, Catherine C. Y. Chang, Pei Zhou, Zhen-Zhen Wang, Han-Hui Ma, Hui-Fang Sha¶, Jiu-Xian Feng¶, Yi Wang, Xin-Ying Yang, Li Wang, Ruhong Dong, Kim Ornvold||, Bo-Liang Li**, and Ta-Yuan Chang

From the State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Rd., Shanghai 200031, China, the Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, the ^¶Shanghai Institute of Thoracic Tumor, Shanghai Chest Hospital, Shanghai 200030, China, and the ^||Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03766

A rare form of human ACAT1 mRNA, containing the optional long 5'-untranslated region, is produced as a 4.3-kelonucleotide chimeric mRNA through a novel interchromosomal trans-splicing of two discontinuous RNAs transcribed from chromosomes 1 and 7 (Li, B. L., Li, X. L., Duan, Z. J., Lee, O., Lin, S., Ma, Z. M., Chang, C. C., Yang, X. Y., Park, J. P., Mohandas, T. K., Noll, W., Chan, L., and Chang, T. Y. (1999) J. Biol. Chem. 274, 11060–11071). To investigate its function, we express the chimeric ACAT1 mRNA in Chinese hamster ovary cells and show that it can produce a larger ACAT1 protein, with an apparent molecular mass of 56 kDa on SDS-PAGE, in addition to the normal, 50-kDa ACAT1 protein, which is produced from the ACAT1 mRNAs without the optional long 5'-untranslated repeat. To produce the 56-kDa ACAT1, acat1 sequences located at both chromosomes 7 and 1 are required. The 56-kDa ACAT1 can be recognized by specific antibodies prepared against the predicted additional amino acid sequence located upstream of the N-terminal of the ACAT1_ORF. The translation initiation codon for the 56-kDa protein is GGC, which encodes for glycine, as deduced by mutation analysis and mass spectrometry. Similar to the 50-kDa protein, when expressed alone, the 56-kDa ACAT1 is located in the endoplasmic reticulum and is enzymatically active. The 56-kDa ACAT1 is present in native human cells, including human monocyte-derived macrophages. Our current results show that the function of the chimeric ACAT1 mRNA is to increase the ACAT enzyme diversity by producing a novel isoenzyme. To our knowledge, our result provides the first mammalian example that a trans-spliced mRNA produces a functional protein.

Received for publication, July 19, 2004

^* This work was supported by Programs 973 (Grant 2002CB51300003) and 863 (Grant 2001AA221061) and Foundations National Natural Science Foundation of China (Grants 30170459 and 30393112), State Science and Technology Committee (Grant 02DJ14068), and Chinese Academy of Sciences (to B.-L. L.), and by National Institutes of Health Grant HL60306 (to T.-Y. C.). 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.

^** To whom correspondence may be addressed. Tel.: 86-21-5492-1278; Fax: 86-21-5492-1011; E-mail: blli{at}sibs.ac.cn. To whom correspondence may be addressed: Dept. of Biochemistry, Dartmouth Medical School, 304 Vail, Hanover, NH 03755. Tel.: 603-650-1622; Fax: 603-650-1483; E-mail: Ta.Yuan.Chang{at}dartmouth.edu.

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