Redox modification of nuclear actin by MICAL-2 regulates SRF signaling

Cell (Impact Factor: 32.24). 01/2014; 156(3). DOI: 10.1016/j.cell.2013.12.035
Source: PubMed


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.

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    • "The serum response results in the interaction of SRF protein with the b-actin promoter, through the disassembly of the MAL-actin interaction, resulting also in the assembly of cytoplasmic b-actin filaments (F-actin) from the now-available Gactin monomers. Interestingly, in recent years, the role of actin has been demonstrated in the regulation of gene expression via the nuclear pool of the actin protein (Hendzel et al., 1999; Huet et al., 2012; Jockusch et al., 2006; Lundquist et al., 2014; McDonald et al., 2006; Khanna et al., 2014; Treisman, 2013). Specifically in SRF signaling, G-actin in a mutant nonpolymerizing form, or as NLS-actin, negatively regulates SRF (Posern et al., 2002). "
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