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Cell Death Differ. 2017 Mar;24(3):433-444. doi: 10.1038/cdd.2016.139. Epub 2016 Dec 2.

Palmitoylation of caspase-6 by HIP14 regulates its activation.

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Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
Translational Laboratories in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore.
Department of Medicine at Yong Loo Lin School of Medicine, National University of Singapore, Singapore 138648, Singapore.
Bioinformatics Institute, Agency for Science, Technology and Research, 30 Biopolis Street, #07-01 Matrix, Singapore 138671, Singapore.
Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 117543, Singapore.
School of Biological Sciences, Nanyang Technological University, 50 Nanyang Drive, Singapore 637551, Singapore.


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.

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