Heterogeneous nuclear ribonucleoprotein A2 is a common transcriptional coactivator in the nuclear transcription response to mitochondrial respiratory stress.
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, which regulates transcription factors, including a new nuclear factor-kappaB (NF-kappaB) pathway, different from the canonical and noncanonical pathways. In this study using a combination of small interfering RNA-mediated mRNA knock down, transcriptional analysis, and chromatin immunoprecipitation, we report a common mechanism for the regulation of previously established stress response genes Cathepsin L, RyR1, and Glut4. Stress-regulated transcription involves the cooperative interplay between NF-kappaB (cRel: p50), C/EBPdelta, cAMP response element-binding protein, and nuclear factor of activated T cells. 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 that involves hnRNP A2 as a transcription coactivator.
Guha
Manti
M
Department of Animal Biology and Marie Lowe Center for Comparative Oncology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Pan
Hua
H
Fang
Ji-Kang
JK
Avadhani
Narayan G
NG
D000818:Animals; D056668:Cathepsin L / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics*; D019069:Cell Respiration / Q000235:genetics; D020868:Gene Silencing; D051275:Glucose Transporter Type 4 / Q000235:genetics; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics*; D008957:Models, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D015398:Signal Transduction; D013312:Stress, Physiological / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics
D051275:Glucose Transporter Type 4; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D019837:Ryanodine Receptor Calcium Release Channel; D015534:Trans-Activators; C439768:hnRNP A2; D056668:Cathepsin L