The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase

Riyad N H Seervai; Rahul K Jangid; Menuka Karki; Durga Nand Tripathi; Sung Yun Jung; Sarah E Kearns; Kristen J Verhey; Michael A Cianfrocco; Bryan A Millis; Matthew J Tyska; Frank M Mason; W Kimryn Rathmell; In Young Park; Ruhee Dere; Cheryl Lyn Walker

doi:10.1126/sciadv.abb7854

The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase

Sci Adv. 2020 Oct 2;6(40):eabb7854. doi: 10.1126/sciadv.abb7854. Print 2020 Oct.

Authors

Riyad N H Seervai^{1

2

3}, Rahul K Jangid², Menuka Karki², Durga Nand Tripathi^{4

2}, Sung Yun Jung⁵, Sarah E Kearns^{6

7

8}, Kristen J Verhey⁶, Michael A Cianfrocco^{7

8}, Bryan A Millis^{9

10}, Matthew J Tyska⁹, Frank M Mason¹¹, W Kimryn Rathmell¹¹, In Young Park¹², Ruhee Dere¹², Cheryl Lyn Walker^{1

2

13

14

15}

Affiliations

¹ Department 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.
² Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA.
³ Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
⁶ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁷ Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
⁸ Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
⁹ Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA.
¹⁰ Vanderbilt Biophotonics Center, Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37240, USA.
¹¹ Vanderbilt-Ingram Cancer Center, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
¹² Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA. riyad.seervai@bcm.edu cheryl.walker@bcm.edu ipark@bcm.edu dere@bcm.edu.
¹³ Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁵ Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

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.

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Actins* / metabolism
Cytoskeleton / metabolism
GTP-Binding Proteins / metabolism*
Histone-Lysine N-Methyltransferase / metabolism*
Lysine* / metabolism
Methylation
Protein Processing, Post-Translational

Substances

Actins
Histone-Lysine N-Methyltransferase
GTP-Binding Proteins
Lysine

Abstract

Publication types

MeSH terms

Substances

Grants and funding