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PMID: 16699508 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function.

Nature neuroscience ·Vol. 9 ·No. 6 ·2006-06-00 ·Pages 824-31

Yanai A, Huang K, Kang R, Singaraja RR, Arstikaitis P, Gan L, Orban PC, Mullard A, Cowan CM, Raymond LA, Drisdel RC, Green WN, Ravikumar B, Rubinsztein DC, El-Husseini A, Hayden MR

Abstract

Post-translational modification by the lipid palmitate is crucial for the correct targeting and function of many proteins. Here we show that huntingtin (htt) is normally palmitoylated at cysteine 214, which is essential for its trafficking and function. The palmitoylation and distribution of htt are regulated by the palmitoyl transferase huntingtin interacting protein 14 (HIP14). Expansion of the polyglutamine tract of htt, which causes Huntington disease, results in reduced interaction between mutant htt and HIP14 and consequently in a marked reduction in palmitoylation. Mutation of the palmitoylation site of htt, making it palmitoylation resistant, accelerates inclusion formation and increases neuronal toxicity. Downregulation of HIP14 in mouse neurons expressing wild-type and mutant htt increases inclusion formation, whereas overexpression of HIP14 substantially reduces inclusions. These results suggest that the expansion of the polyglutamine tract in htt results in decreased palmitoylation, which contributes to the formation of inclusion bodies and enhanced neuronal toxicity.

MeSH Terms
Acyltransferases Adaptor Proteins, Signal Transducing Amino Acid Sequence/physiology Animals Animals, Newborn COS Cells Carrier Proteins/genetics,metabolism Cells, Cultured Cerebral Cortex/cytology,metabolism Chlorocebus aethiops Cysteine/metabolism Down-Regulation/genetics Humans Huntingtin Protein Inclusion Bodies/genetics,metabolism Mice Mice, Transgenic Mutation/genetics Nerve Tissue Proteins/chemistry,genetics,metabolism Neurons/cytology,metabolism Nuclear Proteins/chemistry,genetics,metabolism Palmitic Acid/metabolism Peptides/metabolism Protein Processing, Post-Translational/physiology Protein Transport/physiology Rats Trinucleotide Repeat Expansion/genetics
Chemicals
Adaptor Proteins, Signal Transducing Carrier Proteins Htt protein, mouse Huntingtin Protein Nerve Tissue Proteins Nuclear Proteins Peptides polyglutamine Palmitic Acid Acyltransferases ZDHHC17 protein, human Cysteine
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Yanai Anat
Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
Huang Kun
Kang Rujun
Singaraja Roshni R
Arstikaitis Pamela
Gan Lu
Orban Paul C
Mullard Asher
Cowan Catherine M
Raymond Lynn A
Drisdel Renaldo C
Green William N
Ravikumar Brinda
Rubinsztein David C
El-Husseini Alaa
Hayden Michael R
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Article Info
Journal
Nature neuroscience
Abbr.
Nat Neurosci
ISSN
1097-6256
DOI
10.1038/nn1702
Published
2006-06-00
Epub
2006-00-14
Pages
824-31
Language
English
Region
United States
NLM ID
9809671
PMCID
PMC2279235
Subset
IM
Grants
NINDS NIH HHS · R01 NS043782-01A2 · United States
Wellcome Trust · United Kingdom
NINDS NIH HHS · R01 NS043782-03 · United States
NINDS NIH HHS · R01 NS043782 · United States
NINDS NIH HHS · R01 NS043782-04 · United States
NINDS NIH HHS · R01 NS043782-05 · United States
NINDS NIH HHS · R01 NS043782-02 · United States
External Links
PubMed source DOI: 10.1038/nn1702 PMC Full Text View journal details
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