Intramolecular control of protein stability, subnuclear compartmentalization, and coactivator function of peroxisome proliferator-activated receptor γ coactivator 1α

Motoaki Sano, Satori Tokudome, Noriaki Shimizu, Noritada Yoshikawa, Chie Ogawa, Kousuke Shirakawa, Jin Endo, Takaharu Katayama, Shinsuke Yuasa, Masaki Ieda, Shinji Makino, Fumiyuki Hattori, Hirotoshi Tanaka, Keiichi Fukuda

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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-1αC-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.

Original languageEnglish
Pages (from-to)25970-25980
Number of pages11
JournalJournal of Biological Chemistry
Issue number35
Publication statusPublished - 2007 Aug 31


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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