Abstract
Although the properties of the actin cytoskeleton in the cytoplasm are well characterized, the regulation and function of nuclear actin filaments are only recently emerging. We previously demonstrated serum-induced, transient assembly of filamentous actin within somatic cell nuclei. However, the extracellular cues, cell surface receptors as well as underlying signaling mechanisms have been unclear. Here we demonstrate that physiological ligands for G protein-coupled receptors (GPCRs) promote nuclear F-actin assembly via heterotrimeric Gαq proteins. Signal-induced nuclear actin responses require calcium release from the endoplasmic reticulum (ER) targeting the ER-associated formin INF2 at the inner nuclear membrane (INM). Notably, calcium signaling promotes the polymerization of linear actin filaments emanating from the INM towards the nuclear interior. We show that GPCR and calcium elevations trigger nuclear actin-dependent alterations in chromatin organization, uncovering a general cellular mechanism by which physiological ligands and calcium promote nuclear F-actin assembly for rapid responses towards chromatin dynamics.
Highlights
The properties of the actin cytoskeleton in the cytoplasm are well characterized, the regulation and function of nuclear actin filaments are only recently emerging
Our study reveals that several G protein-coupled receptors (GPCRs) agonists, such as thrombin, LPA, or ATP trigger transient bursts of nuclear F-actin formation downstream of Gαq/11 to promote rapid changes in chromatin dynamics
Given the rapid and transient kinetics of seruminduced NAA, we tested whether induction of calcium elevations triggers nuclear actin dynamics
Summary
The properties of the actin cytoskeleton in the cytoplasm are well characterized, the regulation and function of nuclear actin filaments are only recently emerging. We demonstrate that physiological ligands for G protein-coupled receptors (GPCRs) promote nuclear F-actin assembly via heterotrimeric Gαq proteins. Signal-induced nuclear actin responses require calcium release from the endoplasmic reticulum (ER) targeting the ER-associated formin INF2 at the inner nuclear membrane (INM). We show that GPCR and calcium elevations trigger nuclear actin-dependent alterations in chromatin organization, uncovering a general cellular mechanism by which physiological ligands and calcium promote nuclear Factin assembly for rapid responses towards chromatin dynamics. The actin regulator inverted formin 2 (INF2) is emerging as a factor controlled by calcium signaling that promotes perinuclear F-actin in response to increased intracellular calcium levels[15,16]. Our study reveals that several GPCR agonists, such as thrombin, LPA, or ATP trigger transient bursts of nuclear F-actin formation downstream of Gαq/11 to promote rapid changes in chromatin dynamics
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