The assembly of a three-dimensional actin cytoskeleton is largely mediated by local Rho GTPases. Restriction of microvilli to the epithelial apical surface requires local regulation of actin structure. On epithelial cells, the presence of microvilli depends on RhoA activation of its effector kinases LOK and SLK that phosphorylate ezrin to function as a membrane-actin linker. Further, previous work has revealed that active ezrin negatively regulates RhoA, but the mechanism was unknown. Here, we show this regulation is mediated by recruitment and activation of ARHGAP18 by active ezrin, which stimulates its GTPase activity towards RhoA. Loss of ARHGAP18 enhances ezrin phosphorylation and results in abundant stubby microvilli that turn over rapidly. This phenotype can be rescued by re-expression of ARHAGP18, and by a construct that targets just the GTPase domain to active ezrin, but not a GAP-dead version. Loss of ARHGAP18 also results in enhanced phosphorylation of myosin light chain, the classic response to elevated RhoA levels. This leads to inappropriate assembly of non-muscle myosin-II into microvilli and the disruption of the normal apical actomyosin organization. Thus, the localization and activation of ARGHAP18 by active ezrin constitutes a local auto-regulatory module to fine tune RhoA to ensure appropriate microvilli organization.
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