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J. Biol. Chem., Vol. 282, Issue 35, 25970-25980, August 31, 2007

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Intramolecular Control of Protein Stability, Subnuclear Compartmentalization, and Coactivator Function of Peroxisome Proliferator-activated Receptor Coactivator 1^*

Motoaki Sano¹, Satori Tokudome, Noriaki Shimizu^¶, Noritada Yoshikawa^¶, Chie Ogawa, Kousuke Shirakawa, Jin Endo^||, Takaharu Katayama^||, Shinsuke Yuasa^||, Masaki Ieda^||, Shinji Makino, Fumiyuki Hattori, Hirotoshi Tanaka^¶2, and Keiichi Fukuda²

From the Department of Regenerative Medicine and Advanced Cardiac Therapeutics and the ^||Cardiology Division, and Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan, and the ^¶Division of Clinical Immunology, Advanced Clinical Research Center, and Department of Rheumatology and Allergy, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

Peroxisome proliferator-activated receptor coactivator (PGC)-1 is a critical transcriptional regulator of energy metabolism. Here we found that PGC-1 is a short lived and aggregation-prone protein. PGC-1 localized throughout the nucleoplasm and was rapidly destroyed via the ubiquitin-proteasome pathway. Upon proteasome inhibition, PGC-1 formed insoluble polyubiquitinated aggregates. Ubiquitination of PGC-1 depended on the integrity of the C terminus-containing arginine-serine-rich domains and an RNA recognition motif. Interestingly, ectopically expressed C-terminal fragment of PGC-1 was autonomously ubiquitinated and aggregated with promyelocytic leukemia protein. Cooperation of the N-terminal region containing two PEST-like motifs was required for prevention of aggregation and targeting of the polyubiquitinated PGC-1 for degradation. This region thereby negatively controlled the aggregation properties of the C-terminal region to regulate protein turnover and intranuclear compartmentalization of PGC-1. Exogenous expression of the PGC-1 C-terminal fragment interfered with degradation of full-length PGC-1 and enhanced its coactivation properties. We concluded that PGC-1 function is critically regulated at multiple steps via intramolecular cooperation among several distinct structural domains of the protein.

Received for publication, May 2, 2007 , and in revised form, July 5, 2007.

^* This work was supported by Grant-in-aid for Scientific Research 18390239 from the Japan Society for the Promotion of Science and a Precursory Research for Embryonic Science and Technology (Metabolism and Cellular function) grant from the Japanese Science and Technology Agency (to M. S.), by Grant-in-aid for Creative Scientific Research 17GS0419 (Japan Society for the Promotion of Science) (to H. T.), and by a grant-in-aid from the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation (to K. F.). 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.

² These two authors contributed equally to this work.

¹ To whom correspondence should be addressed: Dept. of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi Shinjuku-ku, Tokyo, 160-8582, Japan. Tel.: 81-3-5363-3874; Fax: 81-3-5363-3875; E-mail: msano{at}sc.itc.keio.ac.jp.

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