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

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

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
Volume282
Issue number35
DOIs
Publication statusPublished - 2007 Aug 31

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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