HHAT palmitoylates Hh N-terminal fragment

Stable Identifier
Reaction [transition]
Homo sapiens
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In addition to being modified by cholesterol at its C-terminal end, the N-terminal fragment of Hh (Hh-Np) is also palmitoylated by the O-acyltransferase HHAT (Pepinsky et al, 1998; Charmoun et al 2001; Chen et al, 2004; Hardy and Resh, 2007). HHAT-mediated palmitoylation of Hh can be recapitulated in vitro and in vivo, and the cholesterol- and palmitoyl-modified N-terminal fragment represents the predominant secreted form of Hh in vivo (Buglino and Resh, 2008; Buglino and Resh, 2010; Taipale et al, 2000). Mutation or depletion of the HHAT enzyme and mutation of the palmitoyl acceptor cysteine in Hh itself abrogates palmitoylation of the ligand and reduces Hh signaling (Chen et al, 2004; Chamoun et al, 2001; Pepinsky et al, 1998; Callier et al, 2014).
Literature References
PubMed ID Title Journal Year
24784881 Loss of Function Mutation in the Palmitoyl-Transferase HHAT Leads to Syndromic 46,XY Disorder of Sex Development by Impeding Hedgehog Protein Palmitoylation and Signaling

Rolland, A, Bernard, P, Callier, P, Antonarakis, SE, Nef, S, Faivre, L, Resh, MD, Desdoits-Lethimonier, C, Stévant, I, Borel, C, Conne, B, Thauvin-Robinet, C, Calvel, P, Santoni, F, Kuhne, F, Wilhelm, D, Mugneret, F, Kurosaka, H, Jaruzelska, J, Jégou, B, Vannier, A, Trainor, PA, Guipponi, M, Huet, F, Mazaud-Guittot, S, Matevossian, A, Makrythanasis, P, Lambert, S, Zimmermann, C

PLoS Genet. 2014
15075292 Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates

Li, YJ, Xu, SM, Chuang, PT, Kawakami, T, Chen, MH

Genes Dev. 2004
20585641 Identification of conserved regions and residues within Hedgehog acyltransferase critical for palmitoylation of Sonic Hedgehog

Resh, MD, Buglino, JA

PLoS ONE 2010
10984056 Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine

Milenkovic, L, Beachy, PA, Mann, RK, Cooper, MK, Scott, MP, Wang, B, Taipale, J, Chen, JK

Nature 2000
9593755 Identification of a palmitic acid-modified form of human Sonic hedgehog

Pepinsky, RB, Galdes, A, Williams, KP, Garber, EA, Wen, D, Wang, EA, Bixler, SA, Miatkowski, K, Rayhorn, P, Taylor, FR, Ambrose, CM, Zeng, C, Baker, DP

J. Biol. Chem. 1998
23112049 Identification of N-terminal residues of Sonic Hedgehog important for palmitoylation by Hedgehog acyltransferase

Resh, MD, Hardy, RY

J. Biol. Chem. 2012
18534984 Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog

Resh, MD, Buglino, JA

J. Biol. Chem. 2008
11486055 Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal

Beachy, PA, Bellotto, M, Nellen, D, Chamoun, Z, von Kessler, DP, Mann, RK, Basler, K

Science 2001
Catalyst Activity

O-acyltransferase activity of HHAT [endoplasmic reticulum membrane]

Orthologous Events
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