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

Abstract

The transcriptional co-activator PGC-1␣ 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␣ (NT-PGC-1␣) produced by alternative 3 splicing that introduces an in-frame stop codon into PGC-1␣ mRNA. The expressed protein includes the first 267 amino acids of PGC-1␣ and 3 additional amino acids from the splicing insert. NT-PGC-1␣ 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␣ are dynamically regulated in the context of physiological signals that regulate fulllength PGC-1␣, 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␣ is a co-expressed, previously unrecognized form of PGC-1␣ with functions that are both unique from and complementary to PGC-1␣.

The hitchhiker’s guide to PGC-1α isoform structure and biological functions

“…Indeed, expression of NT-PGC-1α-a or PGC-1α1 in differentiated brown adipocytes drives similar gene programs, with enhanced mitochondrial biogenesis (Fig. 2) and increased carnitine palmitoyltransferase-1b (CPT-1b) and uncoupling protein 1 (UCP1) expression [45]. NT-Pgc-1α-a expression is induced by exercise training, does not depend on β-adrenergic stimulation, and promotes a classical oxidative phenotype in C2C12 cells [47].…”

“…NT-PGC-1α lacks all the central and C-terminal PGC-1α1 protein modules, including the RS/RRM domains and the NLS [1]. The absence of these sequences unmasks a nuclear export signal (NES) that under basal conditions localises NT-PGC-1α mainly to the cytosol (90%) [45]. Cold exposure or β-adrenergic stimulation of BAT triggers a double mechanism that regulates NT-PGC-1α transcriptional activity.…”

“…Cold exposure or β-adrenergic stimulation of BAT triggers a double mechanism that regulates NT-PGC-1α transcriptional activity. On the one hand, in vitro stimulation of brown adipocytes with a cAMP analogue induces rapid shuttling of cytoplasmic NT-PGC-1α into the nucleus [45]. Additionally, cold exposure induces BAT expression of equivalent levels of full-length and NT-PGC-1α isoforms.…”

“…Although NT-PGC-1α proteins lack the C-terminal domain that in PGC-1α1 is required for interaction with the Mediator complex [9], they still coactivate PPARα and PPARγ transcriptional activity [45]. However, this association is strictly ligand-dependent, probably because NT-PGC-1α lacks the amino acid sequences that in PGC-1α1 mediate ligandindependent coactivation of PPARs (aa 338-403 in PGC-1α1) [48].…”

“…Using a BAT cDNA library, Zhang and collaborators cloned a Pgc-1α variant expressed under the control of the proximal gene promoter that contains an alternative splicing event between exons 6 and 7 [45], which introduces a premature stop codon (Fig. 1).…”