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

By M. Sano, S. Tokudome, N. Shimizu, N. Yoshikawa, Chie Ogawa, Kousuke Shirakawa, J. Endo, T. Katayama, S. Yuasa, M. Ieda and 4 more. Journal of Biological Chemistry, 2007

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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-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.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/88ca9d81f30ea887d5b7835d3444ae6f4bf1003b

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In Physiology

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A practical model of low‐volume high‐intensity interval training induces mitochondrial biogenesis in human skeletal muscle: potential mechanisms (2010, background): “…activation; rather PGC-1α activity may be primarily determined by its subcellular location (Rim et al. 2004; Wright et al. 2007; Cowell et al. 2007; Sano et al. 2007; Anderson et al. 2008; Olson et al. 2008) and several post-translational modifications (Knutti et al. 2001; Jäger et al. 2007;…”