Redox modification of nuclear actin by MICAL-2 regulates SRF signaling.
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Lundquist MR, Storaska AJ, Liu TC, Larsen SD, Evans T, Neubig RR, Jaffrey SR
Redox modification of nuclear actin by MICAL-2 regulates SRF signaling.
Cell. 2014 Jan 30;156(3):563-76. doi: 10.1016/j.cell.2013.12.035. Epub 2014 Jan 16.
- PubMed ID
- 24440334 [ View in PubMed]
- Abstract
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.