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

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

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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.

Original language	English (US)
Article number	eabb7854
Journal	Science Advances
Volume	6
Issue number	40
DOIs	https://doi.org/10.1126/sciadv.abb7854
State	Published - Sep 30 2020
Externally published	Yes

ASJC Scopus subject areas

General

Access to Document

10.1126/sciadv.abb7854

Cite this

Seervai, R. N. H., Jangid, R. K., Karki, M., Tripathi, D. N., Jung, S. Y., Kearns, S. E., Verhey, K. J., Cianfrocco, M. A., Millis, B. A., Tyska, M. J., Mason, F. M., Kimryn Rathmell, W., Park, I. Y., Dere, R., & Walker, C. L. (2020). The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase. Science Advances, 6(40), Article eabb7854. https://doi.org/10.1126/sciadv.abb7854

@article{a65fec6d21c94b26864b51fe9143d0dc,

title = "The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase",

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.",

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

note = "Publisher Copyright: {\textcopyright} 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).",

year = "2020",

month = sep,

day = "30",

doi = "10.1126/sciadv.abb7854",

language = "English (US)",

volume = "6",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "40",

}

TY - JOUR

T1 - The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase

AU - Seervai, Riyad N.H.

AU - Jangid, Rahul K.

AU - Karki, Menuka

AU - Tripathi, Durga Nand

AU - Jung, Sung Yun

AU - Kearns, Sarah E.

AU - Verhey, Kristen J.

AU - Cianfrocco, Michael A.

AU - Millis, Bryan A.

AU - Tyska, Matthew J.

AU - Mason, Frank M.

AU - Kimryn Rathmell, W.

AU - Park, In Young

AU - Dere, Ruhee

AU - Walker, Cheryl Lyn

N1 - Publisher 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).

PY - 2020/9/30

Y1 - 2020/9/30

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85092221055&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85092221055&partnerID=8YFLogxK

U2 - 10.1126/sciadv.abb7854

DO - 10.1126/sciadv.abb7854

M3 - Article

C2 - 33008892

AN - SCOPUS:85092221055

SN - 2375-2548

VL - 6

JO - Science Advances

JF - Science Advances

IS - 40

M1 - eabb7854

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this