Palmitoylation of caspase-6 by HIP14 regulates its activation

Niels H Skotte; Shaun S Sanders; Roshni R Singaraja; Dagmar E Ehrnhoefer; Kuljeet Vaid; Xiaofan Qiu; Srinivasaragavan Kannan; Chandra Verma; Michael R Hayden

doi:10.1038/cdd.2016.139

Palmitoylation of caspase-6 by HIP14 regulates its activation

Niels H Skotte, Shaun S Sanders, Roshni R Singaraja, Dagmar E Ehrnhoefer, Kuljeet Vaid, Xiaofan Qiu, Srinivasaragavan Kannan, Chandra Verma, Michael R Hayden

19 Citationer (Scopus)

Abstract

Caspase-6 (CASP6) has an important role in axonal degeneration during neuronal apoptosis and in the neurodegenerative diseases Alzheimer and Huntington disease. Decreasing CASP6 activity may help to restore neuronal function in these and other diseases such as stroke and ischemia, where increased CASP6 activity has been implicated. The key to finding approaches to decrease CASP6 activity is a deeper understanding of the mechanisms regulating CASP6 activation. We show that CASP6 is posttranslationally palmitoylated by the palmitoyl acyltransferase HIP14 and that the palmitoylation of CASP6 inhibits its activation. Palmitoylation of CASP6 is decreased both in Hip14 -/- mice, where HIP14 is absent, and in YAC128 mice, a model of Huntington disease, where HIP14 is dysfunctional and where CASP6 activity is increased. Molecular modeling suggests that palmitoylation of CASP6 may inhibit its activation via steric blockage of the substrate-binding groove and inhibition of CASP6 dimerization, both essential for CASP6 function. Our studies identify palmitoylation as a novel CASP6 modification and as a key regulator of CASP6 activity.

Originalsprog	Engelsk
Tidsskrift	Cell Death and Differentiation
Vol/bind	24
Sider (fra-til)	433-444
Antal sider	12
ISSN	1350-9047
DOI	https://doi.org/10.1038/cdd.2016.139
Status	Udgivet - 1 mar. 2017
Udgivet eksternt	Ja

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10.1038/cdd.2016.139

cdd2016139.pdfForlagets udgivne version, 4,32 MB

Citationsformater

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title = "Palmitoylation of caspase-6 by HIP14 regulates its activation",

abstract = "Caspase-6 (CASP6) has an important role in axonal degeneration during neuronal apoptosis and in the neurodegenerative diseases Alzheimer and Huntington disease. Decreasing CASP6 activity may help to restore neuronal function in these and other diseases such as stroke and ischemia, where increased CASP6 activity has been implicated. The key to finding approaches to decrease CASP6 activity is a deeper understanding of the mechanisms regulating CASP6 activation. We show that CASP6 is posttranslationally palmitoylated by the palmitoyl acyltransferase HIP14 and that the palmitoylation of CASP6 inhibits its activation. Palmitoylation of CASP6 is decreased both in Hip14 -/- mice, where HIP14 is absent, and in YAC128 mice, a model of Huntington disease, where HIP14 is dysfunctional and where CASP6 activity is increased. Molecular modeling suggests that palmitoylation of CASP6 may inhibit its activation via steric blockage of the substrate-binding groove and inhibition of CASP6 dimerization, both essential for CASP6 function. Our studies identify palmitoylation as a novel CASP6 modification and as a key regulator of CASP6 activity.",

author = "Skotte, {Niels H} and Sanders, {Shaun S} and Singaraja, {Roshni R} and Ehrnhoefer, {Dagmar E} and Kuljeet Vaid and Xiaofan Qiu and Srinivasaragavan Kannan and Chandra Verma and Hayden, {Michael R}",

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T1 - Palmitoylation of caspase-6 by HIP14 regulates its activation

AU - Skotte, Niels H

AU - Sanders, Shaun S

AU - Singaraja, Roshni R

AU - Ehrnhoefer, Dagmar E

AU - Vaid, Kuljeet

AU - Qiu, Xiaofan

AU - Kannan, Srinivasaragavan

AU - Verma, Chandra

AU - Hayden, Michael R

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Caspase-6 (CASP6) has an important role in axonal degeneration during neuronal apoptosis and in the neurodegenerative diseases Alzheimer and Huntington disease. Decreasing CASP6 activity may help to restore neuronal function in these and other diseases such as stroke and ischemia, where increased CASP6 activity has been implicated. The key to finding approaches to decrease CASP6 activity is a deeper understanding of the mechanisms regulating CASP6 activation. We show that CASP6 is posttranslationally palmitoylated by the palmitoyl acyltransferase HIP14 and that the palmitoylation of CASP6 inhibits its activation. Palmitoylation of CASP6 is decreased both in Hip14 -/- mice, where HIP14 is absent, and in YAC128 mice, a model of Huntington disease, where HIP14 is dysfunctional and where CASP6 activity is increased. Molecular modeling suggests that palmitoylation of CASP6 may inhibit its activation via steric blockage of the substrate-binding groove and inhibition of CASP6 dimerization, both essential for CASP6 function. Our studies identify palmitoylation as a novel CASP6 modification and as a key regulator of CASP6 activity.

AB - Caspase-6 (CASP6) has an important role in axonal degeneration during neuronal apoptosis and in the neurodegenerative diseases Alzheimer and Huntington disease. Decreasing CASP6 activity may help to restore neuronal function in these and other diseases such as stroke and ischemia, where increased CASP6 activity has been implicated. The key to finding approaches to decrease CASP6 activity is a deeper understanding of the mechanisms regulating CASP6 activation. We show that CASP6 is posttranslationally palmitoylated by the palmitoyl acyltransferase HIP14 and that the palmitoylation of CASP6 inhibits its activation. Palmitoylation of CASP6 is decreased both in Hip14 -/- mice, where HIP14 is absent, and in YAC128 mice, a model of Huntington disease, where HIP14 is dysfunctional and where CASP6 activity is increased. Molecular modeling suggests that palmitoylation of CASP6 may inhibit its activation via steric blockage of the substrate-binding groove and inhibition of CASP6 dimerization, both essential for CASP6 function. Our studies identify palmitoylation as a novel CASP6 modification and as a key regulator of CASP6 activity.

U2 - 10.1038/cdd.2016.139

DO - 10.1038/cdd.2016.139

M3 - Journal article

C2 - 27911442

SN - 1350-9047

VL - 24

SP - 433

EP - 444

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

ER -

Palmitoylation of caspase-6 by HIP14 regulates its activation

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