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Updated: Dec 7, 2025

Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase
Riyad N H Seervai1,2,3, Rahul K Jangid2, Menuka Karki2
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. riyad.seervai@bcm.edu cheryl.walker@bcm.edu ipark@bcm.edu dere@bcm.edu.
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.
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