title: Wild-type HTT modulates the enzymatic activity of the neuronal palmitoyl transferase HIP14.
abstract: Huntington disease (HD) is caused by polyglutamine expansion in the huntingtin (HTT) protein. Huntingtin-interacting protein 14 (HIP14), one of 23 DHHC domain-containing palmitoyl acyl transferases (PATs), binds to HTT and robustly palmitoylates HTT at cysteine 214. Mutant HTT exhibits reduced palmitoylation and interaction with HIP14, contributing to the neuronal dysfunction associated with HD. In this study, we confirmed that, among 23 DHHC PATs, HIP14 and its homolog DHHC-13 (HIP14L) are the two major PATs that palmitoylate HTT. Wild-type HTT, in addition to serving as a palmitoylation substrate, also modulates the palmitoylation of HIP14 itself. In vivo, HIP14 palmitoylation is decreased in the brains of mice lacking one HTT allele (hdh+/-) and is further reduced in mouse cortical neurons treated with HTT antisense oligos (HTT-ASO) that knockdown HTT expression by ∼95%. Previously, it has been shown that palmitoylation of DHHC proteins may affect their enzymatic activity. Indeed, palmitoylation of SNAP25 by HIP14 is potentiated in vitro in the presence of wild-type HTT. This influence of HTT on HIP14 activity is lost in the presence of CAG expansion. Furthermore, in both brains of hdh+/- mice and neurons treated with HTT-ASO, we observe a significant reduction in palmitoylation of endogenous SNAP25 and GluR1, synaptic proteins that are substrates of HIP14, suggesting wild-type HTT also influences HIP14 enzymatic activity in vivo. This study describes an important biochemical function for wild-type HTT modulation of HIP14 palmitoylation and its enzymatic activity.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.forename: Shaun S
authors.initials: SS
authors.lastname: Sanders
authors.forename: Rujun
authors.initials: R
authors.lastname: Kang
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Carroll
authors.forename: Liza
authors.initials: L
authors.lastname: Sutton
authors.forename: Junmei
authors.initials: J
authors.lastname: Wan
authors.forename: Roshni
authors.initials: R
authors.lastname: Singaraja
authors.forename: Fiona B
authors.initials: FB
authors.lastname: Young
authors.forename: Lili
authors.initials: L
authors.lastname: Liu
authors.forename: Alaa
authors.initials: A
authors.lastname: El-Husseini
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Davis
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D054878:Lipoylation; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D050825:Synaptosomal-Associated Protein 25 / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D050825:Synaptosomal-Associated Protein 25; D000217:Acyltransferases