Impairment of nuclear F-actin formation and its relevance to cellular phenotypes in Hutchinson-Gilford progeria syndrome

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by a mutation of lamin A, which contributes to nuclear architecture and the spatial organization of chromatin in the nucleus. The expression of a lamin A mutant, named progerin, leads to functional and structural disruption of nuclear organization. Since progerin lacks a part of the actin-binding site of lamin A, we hypothesized that nuclear actin dynamics and function are altered in HGPS cells. Nuclear F-actin is required for the organization of nuclear shape, transcriptional regulation, DNA damage repair, and activation of Wnt/β-catenin signaling. Here we show that the expression of progerin decreases nuclear F-actin and impairs F-actin-regulated transcription. When nuclear F-actin levels are increased by overexpression of nuclear-targeted actin or by using jasplakinolide, a compound that stabilizes F-actin, the irregularity of nuclear shape and defects in gene expression can be reversed. These observations provide evidence for a novel relationship between nuclear actin and the etiology of HGPS.

Limited Proteolysis-Coupled Mass Spectrometry Identifies Phosphatidylinositol 4,5-Bisphosphate Effectors in Human Nuclear Proteome

“…The importance of actin in the activity of Pol I and Pol II has also been documented [ 37 , 39 ]. Therefore, the presented PIPsLiP-qMS identification of the PIP2-effectors associated with actin cytoskeleton is in agreement with the previous studies that showed involvement of nucleoskeleton in the regulation of gene expression [ 37 , 38 , 39 , 40 , 41 ]. Moreover, the novel PIP2-binding actin- and cytoskeleton-related proteins identified here are interesting candidates for further studies.…”

Nuclear actin structure regulates chromatin accessibility

“…Mahmood et al analyzed several aspects of chromatin state and showed that knocking down β-actin levels altered chromatin structure via chromatin remodelers such as BAF/ BRG1 and EZH2, the latter which we have also shown to be influenced by changes in actin structure 8 , 40 . As well, expression of progerin, the mutant lamin A involved in Hutchinson-Gilford progeria syndrome, also leads to decreased nuclear actin and gene expression, and can be partially corrected by overexpression of nuclear-targeted actin 46 . Insofar as the state of actin, as we confirm in this work, increased nuclear actin promotes transition from the proliferative state and eventually constrains the non-proliferating cell into differentiative phenotypes; increasing the proportion of the branched F-actin form in the nucleus leads to osteoblast lineage while decreased nuclear F-actin leads to adipogenesis 47 .…”

Nuclear envelope mechanobiology: linking the nuclear structure and function

“…LMNA-dependent phosphorylation of ERK1/2 causes the phosphorylation of FHOD1/3, inhibiting actin bundling at the nuclear envelope [110]. The regulatory role of lamin A/C in connecting to F-actin fibers results in the loss of nuclear positioning [110], nuclear movement [110], and negates jasplakinolideinduced nuclear F-actin formation in fibroblasts leading to reduced transcription [111]. These observations of lamin A/C loss and nuclear morphology alterations are constant throughout mechanical force stimulation.…”