Redox modification of nuclear actin by MICAL-2 regulates SRF signaling.
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.
Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
Mark R
MR
Lundquist
Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA.
Andrew J
AJ
Storaska
Department of Surgery, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
Ting-Chun
TC
Liu
Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
Scott D
SD
Larsen
Department of Surgery, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
Todd
T
Evans
Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
Richard R
RR
Neubig
Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA. Electronic address: srj2003@med.cornell.edu.
Samie R
SR
Jaffrey
D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D020932:Nerve Growth Factor / Q000378:metabolism; D016501:Neurites / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D016415:Sequence Alignment; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators; D014158:Transcription, Genetic; D015027:Zebrafish; D000096985:Calponins
D000199:Actins; D000813:Anilides; D001549:Benzamides; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D006899:Mixed Function Oxygenases; D020932:Nerve Growth Factor; D015514:Oncogene Proteins, Fusion; D010088:Oxidoreductases; D026362:Serum Response Factor; D015534:Trans-Activators; C523455:CCG 1423; C431575:MRTFA protein, human; C587931:MICAL2 protein, human; D000096985:Calponins; C561623:MICAL3 protein, human