SETD2 is an actin lysine methyltransferase

Abstract

SET-domain-containing-2 (SETD2) was identified as the methyltransferase responsible for the histone 3 lysine 36 trimethyl (H3K36me3) mark of the histone code. Most recently, SETD2 has been shown to be a dual-function remodeler that regulates genome stability via methylation of dynamic microtubules during mitosis and cytokinesis. Here we show that actin is a bona fide target for methylation by SETD2 in vitro and in cells. Antibodies against the SETD2 trimethyl lysine epitope recognize methylated actin, with this methyl mark localizing to areas of active actin cytoskeleton reorganization in migrating cells. Disruption of this methylation activity causes defects in actin polymerization and impairscollective cell migration. Together, these data identify SETD2 as a multifunctional cytoskeletal remodeler regulating methylation and polymerization of actin filaments, and provide new avenues for understanding how defects in SETD2 drive disease via aberrant cytoskeletal methylation.

Huntingtin coordinates dendritic spine morphology and function through cofilin-mediated control of the actin cytoskeleton

“…Mutant HTT affects the expression of actin-related proteins (Ratovitski et al, 2016). One study implicated HTT in actin dynamics: by binding to the methyltransferase SETD2, HTT enhances actin methylation and polymerization in HEK cells (Seervai et al, 2020). Here we provide the evidence that HTT influences actin cytoskeletal dynamics in dendritic spines.…”