Key result
CAP2 inactivation in mouse embryonic fibroblasts led to moderately increased G-actin levels and reduced nuclear localization of MRTF-A under basal conditions, though serum-induced nuclear translocation remained intact.
Why the study?
Although cyclase-associated proteins regulate actin dynamics and CAP2 has been implicated in heart physiology and skeletal muscle development, the CAP2-dependent mechanism relevant for SRF activity remained unclear.
CAP2 controls basal MRTF-A localization and SRF activity in an actin-dependent manner in mouse embryonic fibroblasts, providing a potential molecular mechanism for the cardiac defects observed in CAP2 mutant models.
Provides mechanistic insight into CAP2 cardiac defects in mice; leaves open relevance to human cardiomyopathy.
Recent studies identified cyclase-associated proteins (CAPs) as important regulators of actin dynamics that control assembly and disassembly of actin filaments (F-actin). While these studies significantly advanced our knowledge of their molecular functions, the physiological relevance of CAPs largely remained elusive. Gene targeting in mice implicated CAP2 in heart physiology and skeletal muscle development. Heart defects in CAP2 mutant mice were associated with altered activity of serum response factor (SRF), a transcription factor involved in multiple biological processes including heart function, but also skeletal muscle development. By exploiting mouse embryonic fibroblasts (MEFs) from CAP2 mutant mice, we aimed at deciphering the CAP2-dependent mechanism relevant for SRF activity. Reporter assays and mRNA quantification by qPCR revealed reduced SRF-dependent gene expression in mutant MEFs. Reduced SRF activity was associated with moderately increased G-actin levels and reduced nuclear levels of MRTF-A, a transcriptional SRF coactivator that is shuttled out of the nucleus and, hence, inhibited upon G-actin binding. Moreover, pharmacological actin manipulation restored MRTF-A distribution in mutant MEFs. Our data are in line with a model in which CAP2 controls the MRTF-SRF pathway in an actin-dependent manner. While MRTF-A localization and SRF activity was impaired under basal conditions, serum stimulation induced nuclear MRTF-A translocation and SRF activity in mutant MEFs similar to controls. In summary, our data revealed that in MEFs CAP2 controls basal MRTF-A localization and SRF activity, while it was dispensable for serum-induced nuclear MRTF-A translocation and SRF stimulation.
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Kepser et al. (2020) studied this question. CAP2 inactivation vs. Wild-type control MEFs was evaluated on MRTF-A subcellular localization and SRF activity. CAP2 inactivation in mouse embryonic fibroblasts led to moderately increased G-actin levels and reduced nuclear localization of MRTF-A under basal conditions, though serum-induced nuclear translocation remained intact.
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