Redox modification of nuclear actin by MICAL-2 regulates SRF signaling.
- Authors
- Lundquist, M.R., Storaska, A.J., Liu, T.C., Larsen, S.D., Evans, T., Neubig, R.R., Jaffrey, S.R.
- ID
- ZDB-PUB-170525-6
- Date
- 2014
- Source
- Cell 156(3): 563-76 (Journal)
- Registered Authors
- Evans, Todd
- Keywords
- none
- MeSH Terms
-
- Actins/metabolism
- Amino Acid Sequence
- Anilides/pharmacology
- Animals
- Benzamides/pharmacology
- Cell Line
- Cell Nucleus/metabolism*
- Cells, Cultured
- DNA-Binding Proteins/metabolism
- Gene Knockdown Techniques
- Humans
- Mice
- Microfilament Proteins/analysis
- Microfilament Proteins/genetics
- Microfilament Proteins/metabolism*
- Mixed Function Oxygenases/analysis
- Mixed Function Oxygenases/genetics
- Mixed Function Oxygenases/metabolism
- Molecular Sequence Data
- Nerve Growth Factor/metabolism
- Neurites/metabolism
- Oncogene Proteins, Fusion/metabolism
- Oxidation-Reduction
- Oxidoreductases/analysis
- Oxidoreductases/genetics
- Oxidoreductases/metabolism*
- Rats
- Sequence Alignment
- Serum Response Factor/metabolism*
- Signal Transduction*
- Trans-Activators
- Transcription, Genetic
- Zebrafish
- PubMed
- 24440334 Full text @ Cell
The serum response factor (SRF) binds to coactivators, such as myocardin-related transcription factor-A (MRTF-A), and mediates gene transcription elicited by diverse signaling pathways. SRF/MRTF-A-dependent gene transcription is activated when nuclear MRTF-A levels increase, enabling the formation of transcriptionally active SRF/MRTF-A complexes. The level of nuclear MRTF-A is regulated by nuclear G-actin, which binds to MRTF-A and promotes its nuclear export. However, pathways that regulate nuclear actin levels are poorly understood. Here, we show that MICAL-2, an atypical actin-regulatory protein, mediates SRF/MRTF-A-dependent gene transcription elicited by nerve growth factor and serum. MICAL-2 induces redox-dependent depolymerization of nuclear actin, which decreases nuclear G-actin and increases MRTF-A in the nucleus. Furthermore, we show that MICAL-2 is a target of CCG-1423, a small molecule inhibitor of SRF/MRTF-A-dependent transcription that exhibits efficacy in various preclinical disease models. These data identify redox modification of nuclear actin as a regulatory switch that mediates SRF/MRTF-A-dependent gene transcription.