Alternative mRNA Splicing Produces a Novel Biologically Active Short Isoform of PGC-1α

The transcriptional co-activator PGC-1 alpha regulates functional plasticity in adipose tissue by linking sympathetic input to the transcriptional program of adaptive thermogenesis. We report here a novel truncated form of PGC-1 alpha (NT-PGC-1 alpha) produced by alternative 3' splicing that introduces an in-frame stop codon into PGC-1 alpha mRNA. The expressed protein includes the first 267 amino acids of PGC-1 alpha and 3 additional amino acids from the splicing insert. NT-PGC-1 alpha contains the transactivation and nuclear receptor interaction domains but is missing key domains involved in nuclear localization, interaction with other transcription factors, and protein degradation. Expression and subcellular localization of NT-PGC-1 alpha are dynamically regulated in the context of physiological signals that regulate full-length PGC-1 alpha, but the truncated domain structure conveys unique properties with respect to protein-protein interactions, protein stability, and recruitment to target gene promoters. Therefore, NT-PGC-1 alpha is a co-expressed, previously unrecognized form of PGC-1 alpha with functions that are both unique from and complementary to PGC-1 alpha.