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Heterogeneous nuclear ribonucleoprotein A2 is a common transcriptional coactivator in the nuclear transcription response to mitochondrial respiratory stress.
- Source :
-
Molecular biology of the cell [Mol Biol Cell] 2009 Sep; Vol. 20 (18), pp. 4107-19. Date of Electronic Publication: 2009 Jul 29. - Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Animals
Cathepsin L genetics
Cell Respiration genetics
Gene Silencing
Glucose Transporter Type 4 genetics
Heterogeneous-Nuclear Ribonucleoprotein Group A-B chemistry
Humans
Mice
Models, Genetic
Promoter Regions, Genetic genetics
Protein Binding
Protein Interaction Mapping
Protein Structure, Tertiary
Ryanodine Receptor Calcium Release Channel genetics
Signal Transduction
Transcriptional Activation genetics
Cell Nucleus genetics
Heterogeneous-Nuclear Ribonucleoprotein Group A-B metabolism
Mitochondria genetics
Stress, Physiological genetics
Trans-Activators metabolism
Transcription, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 1939-4586
- Volume :
- 20
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Molecular biology of the cell
- Publication Type :
- Academic Journal
- Accession number :
- 19641020
- Full Text :
- https://doi.org/10.1091/mbc.E09-04-0296