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

• Published in: The Journal of biological chemistry Vol. 282; no. 35; pp. 25970 - 25980
• Main Authors: Sano, Motoaki, Tokudome, Satori, Shimizu, Noriaki, Yoshikawa, Noritada, Ogawa, Chie, Shirakawa, Kousuke, Endo, Jin, Katayama, Takaharu, Yuasa, Shinsuke, Ieda, Masaki, Makino, Shinji, Hattori, Fumiyuki, Tanaka, Hirotoshi, Fukuda, Keiichi
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 31.08.2007
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M703634200

Peroxisome proliferator-activated receptor γ coactivator (PGC)-1 is a critical transcriptional regulator of energy metabolism. Here we found that PGC-1α is a short lived and aggregation-prone protein. PGC-1α localized throughout the nucleoplasm and was rapidly destroyed via the ubiquitin-proteasome pathway. Upon proteasome inhibition, PGC-1α formed insoluble polyubiquitinated aggregates. Ubiquitination of PGC-1α 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-1α 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-1α for degradation. This region thereby negatively controlled the aggregation properties of the C-terminal region to regulate protein turnover and intranuclear compartmentalization of PGC-1α. Exogenous expression of the PGC-1α C-terminal fragment interfered with degradation of full-length PGC-1α and enhanced its coactivation properties. We concluded that PGC-1α function is critically regulated at multiple steps via intramolecular cooperation among several distinct structural domains of the protein.