Huntingtin-interacting protein HIP14 is a palmitoyl transferase involved in palmitoylation and trafficking of multiple neuronal proteins.
In neurons, posttranslational modification by palmitate regulates the trafficking and function of signaling molecules, neurotransmitter receptors, and associated synaptic scaffolding proteins. However, the enzymatic machinery involved in protein palmitoylation has remained elusive. Here, using biochemical assays, we show that huntingtin (htt) interacting protein, HIP14, is a neuronal palmitoyl transferase (PAT). HIP14 shows remarkable substrate specificity for neuronal proteins, including SNAP-25, PSD-95, GAD65, synaptotagmin I, and htt. Conversely, HIP14 is catalytically invariant toward paralemmin and synaptotagmin VII. Exogenous HIP14 enhances palmitoylation-dependent vesicular trafficking of several acylated proteins in both heterologous cells and neurons. Moreover, interference with endogenous expression of HIP14 reduces clustering of PSD-95 and GAD65 in neurons. These findings define HIP14 as a mammalian palmitoyl transferase involved in the palmitoylation and trafficking of multiple neuronal proteins.
Huang
Kun
K
Department of Psychiatry, Brain Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Yanai
Anat
A
Kang
Rujun
R
Arstikaitis
Pamela
P
Singaraja
Roshni R
RR
Metzler
Martina
M
Mullard
Asher
A
Haigh
Brendan
B
Gauthier-Campbell
Catherine
C
Gutekunst
Claire-Anne
CA
Hayden
Michael R
MR
El-Husseini
Alaa
A
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D019308:Palmitic Acid / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D013379:Substrate Specificity
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D019308:Palmitic Acid; D000217:Acyltransferases; C473038:ZDHHC17 protein, human; D002334:Carnitine O-Palmitoyltransferase