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MBC in Press, published online ahead of print July 29, 2009
Mol. Biol. Cell 10.1091/mbc.E09-04-0296

A more recent version of this article appeared on September 15, 2009
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Submitted on April 13, 2009
Accepted on July 17, 2009

hnRNP A2 Is a Common Transcriptional Coactivator in the Nuclear Transcription Response to Mitochondrial Respiratory Stress

Manti Guha, Hua Pan, Ji-Kang Fang, and Narayan G. Avadhani

The Department of Animal Biology and the Marie Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104

Monitoring Editor: Thomas D. Fox

Mitochondrial dysfunction and altered transmembrane potential initiate a mitochondrial respiratory stress response, also known as mitochondrial retrograde response, in a wide spectrum of cells. The mitochondrial stress response activates calcineurin (Cn), which regulates transcription factors including a new NF{kappa}B pathway, different from the canonical and noncanonical pathways. In this study using a combination of siRNA mediated mRNA knock down, transcriptional analysis and chromatin immunoprecipitation (ChIP) we report a common mechanism for the regulation of previously established stress response genes, Cathepsin L, RyR1 and Glut 4. Stress regulated transcription involves the cooperative interplay between NF{kappa}B (cRel: p50), C/EBP{delta}, CREB and NFAT. We show that the functional synergy of these factors requires the stress-activated heterogeneous nuclear ribonucleoprotein, hnRNP A2 as a coactivator. HnRNP A2 associates with the enhanceosome mostly through protein-protein interactions with DNA bound factors. Silencing of hnRNP A2 as well as other DNA binding signature factors prevents stress-induced transcriptional activation and reverses the invasiveness of mitochondrial DNA-depleted C2C12 cells. Induction of mitochondrial stress signaling by electron transfer chain inhibitors also involved hnRNPA2 activation. We describe a common mechanism of mitochondrial respiratory stress–induced activation of nuclear target genes which involves hnRNP A2 as a transcription coactivator.

Address correspondence to: Narayan G. Avadhani (narayan{at}vet.upenn.edu)






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