The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33008892.
- Also identified by DOI 10.1126/sciadv.abb7854 and PMC identifier 7852384.
- Licence recorded as CC BY-NC.
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Abstract
The methyltransferase SET domain-containing 2 (SETD2) was originally identified as Huntingtin (HTT) yeast partner B. However, a SETD2 function associated with the HTT scaffolding protein has not been elucidated, and no linkage between HTT and methylation has yet been uncovered. Here, we show that SETD2 is an actin methyltransferase that trimethylates lysine-68 (ActK68me3) in cells via its interaction with HTT and the actin-binding adapter HIP1R. ActK68me3 localizes primarily to the insoluble F-actin cytoskeleton in cells and regulates actin polymerization/depolymerization dynamics. Disruption of the SETD2-HTT-HIP1R axis inhibits actin methylation, causes defects in actin polymerization, and impairs cell migration. Together, these data identify SETD2 as a previously unknown HTT effector regulating methylation and polymerization of actin filaments and provide new avenues for understanding how defects in SETD2 and HTT drive disease via aberrant cytoskeletal methylation.
Medical subject headings
- Actins
- GTP-Binding Proteins
- Histone-Lysine N-Methyltransferase
- Lysine