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

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