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Activated STAT5A interacts with the pyruvate dehydrogenase complex in adipocytes
Author(s) -
Stephens Jacqueline,
Richard Allison
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.728.16
Subject(s) - microbiology and biotechnology , stat5 , mitochondrion , adipogenesis , pyruvate dehydrogenase complex , biology , protein subunit , phosphorylation , chemistry , biochemistry , adipose tissue , gene , enzyme
STAT5 (5A and 5B) mediates signaling by diverse cytokines and growth factors and plays crucial roles in many cellular processes. It is highly expressed in adipocytes, and numerous studies have demonstrated its adipogenic capabilities. Despite recent studies identifying target genes of STAT5 proteins in fat cells, the specificity of action of STAT5 is not well understood. To test the hypothesis that identifying novel STAT5‐interacting proteins would increase our understanding of STAT5 specificity, we affinity purified STAT5A from fat cells under different conditions and used mass spectrometry to discover interacting proteins. One of the proteins identified by this non‐biased approach was PDC‐E2, the E2 subunit of the pyruvate dehydrogenase complex (PDC) that is responsible for the conversion of pyruvate to acetyl‐CoA within the mitochondrial matrix. We validated this interaction in murine and human cultured fat cells and in adipose tissue in vivo. Multiple subunits of PDC interacted with hormone‐activated STAT5A in a dose‐ and time‐dependent manner that coincided with STAT5 tyrosine phosphorylation. Using subcellular fractionation and immunogold electron microscopy, we also observed that STAT5A localized within adipocyte mitochondria. We propose that mitochondrial STAT5A acts as a transcriptional regulator of mitochondrial gene expression. Moreover, it was recently demonstrated that PDC translocates from mitochondria to the nucleus, where it is enzymatically active and capable of generating acetyl‐CoA, which can serve as a substrate for histone acetylation. Currently, we are investigating the role of the nuclear STAT5‐PDC complex in chromatin remodeling and transcriptional regulation within adipocytes.
This work was supported by grant R01DK52968 from NIH to JMS.