Redox Modification of Nuclear Actin by MICAL-2 Regulates SRF Signaling

• Published in: Cell 2014-01, Vol.156 (3), p.563-576
• Main Authors: Lundquist, Mark R., Storaska, Andrew J., Liu, Ting-Chun, Larsen, Scott D., Evans, Todd, Neubig, Richard R., Jaffrey, Samie R.
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.12.035

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. [Display omitted] •MICAL-2 activates SRF/MRTF-A-dependent gene transcription•MICAL-2 induces a redox modification of nuclear actin•MICAL-2 induces the nuclear localization of MRTF-A•The SRF/MRTF-A pathway inhibitor CCG-1423 inhibits MICAL-2 MICAL-2, an atypical actin-regulatory protein, induces redox-dependent depolymerization of nuclear actin, which decreases levels of nuclear G-actin and promotes retention of MRTF-A in the nucleus. Thus, redox modification of nuclear actin is a regulatory switch that mediates SRF/MRTF-A-dependent gene transcription.