Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Originally published in Science Express on 2 August 2001
Science 14 September 2001:
Vol. 293. no. 5537, pp. 2080 - 2084
DOI: 10.1126/science.1064437
Prev | Table of Contents | Next

Reports

Skinny Hedgehog, an Acyltransferase Required for Palmitoylation and Activity of the Hedgehog Signal

Zeina Chamoun,1* Randall K. Mann,2* Denise Nellen,1 Doris P. von Kessler,2 Manolo Bellotto,1 Philip A. Beachy,2dagger Konrad Basler1dagger

One of the most dominant influences in the patterning of multicellular embryos is exerted by the Hedgehog (Hh) family of secreted signaling proteins. Here, we identify a segment polarity gene in Drosophila melanogaster, skinny hedgehog (ski), and show that its product is required in Hh-expressing cells for production of appropriate signaling activity in embryos and in the imaginal precursors of adult tissues. The ski gene encodes an apparent acyltransferase, and we provide genetic and biochemical evidence that Hh proteins from ski mutant cells retain carboxyl-terminal cholesterol modification but lack amino-terminal palmitate modification. Our results suggest that ski encodes an enzyme that acts within the secretory pathway to catalyze amino-terminal palmitoylation of Hh, and further demonstrate that this lipid modification is required for the embryonic and larval patterning activities of the Hh signal.

1 Institut für Molekularbiologie and Zoologisches Institut, Universität Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
2 Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: pbeachy{at}jhmi.edu (P.A.B.), basler{at}molbio.unizh.ch (K.B.)

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Colocalization of ghrelin O-acyltransferase and ghrelin in gastric mucosal cells.
I. Sakata, J. Yang, C. E. Lee, S. Osborne-Lawrence, S. A. Rovinsky, J. K. Elmquist, and J. M. Zigman (2009)
Am J Physiol Endocrinol Metab 297, E134-E141
   Abstract »    Full Text »    PDF »
Wnt Signaling and Stem Cell Control.
R. Nusse, C. Fuerer, W. Ching, K. Harnish, C. Logan, A. Zeng, D. ten Berge, and Y. Kalani (2008)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
Thematic Review Series: Glycerolipids. DGAT enzymes and triacylglycerol biosynthesis.
C.-L. E. Yen, S. J. Stone, S. Koliwad, C. Harris, and R. V. Farese Jr. (2008)
J. Lipid Res. 49, 2283-2301
   Abstract »    Full Text »    PDF »
Hedgehog: functions and mechanisms.
M. Varjosalo and J. Taipale (2008)
Genes & Dev. 22, 2454-2472
   Abstract »    Full Text »    PDF »
Hedgehog signalling in endocrine development and disease.
P. J King, L. Guasti, and E. Laufer (2008)
J. Endocrinol. 198, 439-450
   Abstract »    Full Text »    PDF »
Hhat Is a Palmitoylacyltransferase with Specificity for N-Palmitoylation of Sonic Hedgehog.
J. A. Buglino and M. D. Resh (2008)
J. Biol. Chem. 283, 22076-22088
   Abstract »    Full Text »    PDF »
Member of the membrane-bound O-acyltransferase (MBOAT) family encodes a lysophospholipid acyltransferase with broad substrate specificity..
S. Matsuda, T. Inoue, H.-C. Lee, N. Kono, F. Tanaka, K. Gengyo-Ando, S. Mitani, and H. Arai (2008)
Genes Cells 13, 879-888
   Abstract »    Full Text »    PDF »
An Acyltransferase Controls the Generation of Hematopoietic and Endothelial Lineages in Zebrafish.
J.-W. Xiong, Q. Yu, J. Zhang, and J. D. Mably (2008)
Circ. Res. 102, 1057-1064
   Abstract »    Full Text »    PDF »
From the Cover: Ghrelin octanoylation mediated by an orphan lipid transferase.
J. A. Gutierrez, P. J. Solenberg, D. R. Perkins, J. A. Willency, M. D. Knierman, Z. Jin, D. R. Witcher, S. Luo, J. E. Onyia, and J. E. Hale (2008)
PNAS 105, 6320-6325
   Abstract »    Full Text »    PDF »
The Adventures of Sonic Hedgehog in Development and Repair. III. Hedgehog processing and biological activity.
S. F. Farzan, S. Singh, N. S. Schilling, and D. J. Robbins (2008)
Am J Physiol Gastrointest Liver Physiol 294, G844-G849
   Abstract »    Full Text »    PDF »
A Screen for Modifiers of Hedgehog Signaling in Drosophila melanogaster Identifies swm and mts.
D. J. Casso, S. Liu, D. D. Iwaki, S. K. Ogden, and T. B. Kornberg (2008)
Genetics 178, 1399-1413
   Abstract »    Full Text »    PDF »
Mouse lysocardiolipin acyltransferase controls the development of hematopoietic and endothelial lineages during in vitro embryonic stem-cell differentiation.
C. Wang, P. W. Faloon, Z. Tan, Y. Lv, P. Zhang, Y. Ge, H. Deng, and J.-W. Xiong (2007)
Blood 110, 3601-3609
   Abstract »    Full Text »    PDF »
Porcupine-mediated lipid-modification regulates the activity and distribution of Wnt proteins in the chick neural tube.
L. M. Galli, T. L. Barnes, S. S. Secrest, T. Kadowaki, and L. W. Burrus (2007)
Development 134, 3339-3348
   Abstract »    Full Text »    PDF »
Hedgehog signaling.
M. Varjosalo and J. Taipale (2007)
J. Cell Sci. 120, 3-6
   Full Text »    PDF »
Sprinter: a novel transmembrane protein required for Wg secretion and signaling.
R. M. Goodman, S. Thombre, Z. Firtina, D. Gray, D. Betts, J. Roebuck, E. P. Spana, and E. M. Selva (2006)
Development 133, 4901-4911
   Abstract »    Full Text »    PDF »
Palmitoylation of Ligands, Receptors, and Intracellular Signaling Molecules.
M. D. Resh (2006)
Sci. STKE 2006, re14
   Abstract »    Full Text »    PDF »
How does cholesterol affect the way Hedgehog works?.
F. Wendler, X. Franch-Marro, and J.-P. Vincent (2006)
Development 133, 3055-3061
   Abstract »    Full Text »    PDF »
Negative regulation of Hedgehog signaling by the cholesterogenic enzyme 7-dehydrocholesterol reductase.
T. Koide, T. Hayata, and K. W. Y. Cho (2006)
Development 133, 2395-2405
   Abstract »    Full Text »    PDF »
Thematic review series: Lipid Posttranslational Modifications. Protein palmitoylation by a family of DHHC protein S-acyltransferases.
D. A. Mitchell, A. Vasudevan, M. E. Linder, and R. J. Deschenes (2006)
J. Lipid Res. 47, 1118-1127
   Abstract »    Full Text »    PDF »
Cholesterol modification restricts the spread of Shh gradient in the limb bud.
Y. Li, H. Zhang, Y. Litingtung, and C. Chiang (2006)
PNAS 103, 6548-6553
   Abstract »    Full Text »    PDF »
A Highly Conserved Amino-terminal Region of Sonic Hedgehog Is Required for the Formation of Its Freely Diffusible Multimeric Form.
J. A. Goetz, S. Singh, L. M. Suber, F. J. Kull, and D. J. Robbins (2006)
J. Biol. Chem. 281, 4087-4093
   Abstract »    Full Text »    PDF »
Hedgehog lipid modifications are required for Hedgehog stabilization in the extracellular matrix.
A. Callejo, C. Torroja, L. Quijada, and I. Guerrero (2006)
Development 133, 471-483
   Abstract »    Full Text »    PDF »
Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly.
T. Maity, N. Fuse, and P. A. Beachy (2005)
PNAS 102, 17026-17031
   Abstract »    Full Text »    PDF »
The function and expansion of the Patched- and Hedgehog-related homologs in C. elegans.
O. Zugasti, J. Rajan, and P. E. Kuwabara (2005)
Genome Res. 15, 1402-1410
   Abstract »    Full Text »    PDF »
A Genetic Screen in Drosophila for Identifying Novel Components of the Hedgehog Signaling Pathway.
R. T. Collins and S. M. Cohen (2005)
Genetics 170, 173-184
   Abstract »    Full Text »    PDF »
Mouse Disp1 is required in sonic hedgehog-expressing cells for paracrine activity of the cholesterol-modified ligand.
H. Tian, J. Jeong, B. D. Harfe, C. J. Tabin, and A. P. McMahon (2005)
Development 132, 133-142
   Abstract »    Full Text »    PDF »
Inaugural Article: Biography of Philip A. Beachy.
M. Marino (2004)
PNAS 101, 17897-17899
   Full Text »    PDF »
Dose dependency of Disp1 and genetic interaction between Disp1 and other hedgehog signaling components in the mouse.
H. Tian, T. Tenzen, and A. P. McMahon (2004)
Development 131, 4021-4033
   Abstract »    Full Text »    PDF »
Drosophila Wnt-1 Undergoes a Hydrophobic Modification and Is Targeted to Lipid Rafts, a Process That Requires Porcupine.
L. Zhai, D. Chaturvedi, and S. Cumberledge (2004)
J. Biol. Chem. 279, 33220-33227
   Abstract »    Full Text »    PDF »
B Cell Signaling Is Regulated by Induced Palmitoylation of CD81.
A. Cherukuri, R. H. Carter, S. Brooks, W. Bornmann, R. Finn, C. S. Dowd, and S. K. Pierce (2004)
J. Biol. Chem. 279, 31973-31982
   Abstract »    Full Text »    PDF »
Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates.
M.-H. Chen, Y.-J. Li, T. Kawakami, S.-M. Xu, and P.-T. Chuang (2004)
Genes & Dev. 18, 641-659
   Abstract »    Full Text »    PDF »
Model organisms lead the way to protein palmitoyltransferases.
M. E. Linder and R. J. Deschenes (2004)
J. Cell Sci. 117, 521-526
   Abstract »    Full Text »    PDF »
Drosophila glypicans control the cell-to-cell movement of Hedgehog by a dynamin-independent process.
C. Han, T. Y. Belenkaya, B. Wang, and X. Lin (2004)
Development 131, 601-611
   Abstract »    Full Text »    PDF »
The glypican Dally-like is required for Hedgehog signalling in the embryonic epidermis of Drosophila.
S. C. Desbordes and B. Sanson (2003)
Development 130, 6245-6255
   Abstract »    Full Text »    PDF »
Wnts and Hedgehogs: lipid-modified proteins and similarities in signaling mechanisms at the cell surface.
R. Nusse (2003)
Development 130, 5297-5305
   Abstract »    Full Text »    PDF »
Emerging Roles for Hedgehog-Patched-Gli Signal Transduction in Reproduction.
D. O. Walterhouse, M. L.G. Lamm, E. Villavicencio, and P. M. Iannaccone (2003)
Biol Reprod 69, 8-14
   Abstract »    Full Text »    PDF »
How a Hedgehog might see holoprosencephaly.
E. Roessler and M. Muenke (2003)
Hum. Mol. Genet. 12, R15-25
   Abstract »    Full Text »    PDF »
Identification of Hedgehog Pathway Components by RNAi in Drosophila Cultured Cells.
L. Lum, S. Yao, B. Mozer, A. Rovescalli, D. Von Kessler, M. Nirenberg, and P. A. Beachy (2003)
Science 299, 2039-2045
   Abstract »    Full Text »    PDF »
rasp, a putative transmembrane acyltransferase, is required for Hedgehog signaling.
C. A. Micchelli, I. The, E. Selva, V. Mogila, and N. Perrimon (2003)
Development 129, 843-851
   Abstract »    Full Text »    PDF »
A direct requirement for Hedgehog signaling for normal specification of all ventral progenitor domains in the presumptive mammalian spinal cord.
M. Wijgerde, J. A. McMahon, M. Rule, and A. P. McMahon (2002)
Genes & Dev. 16, 2849-2864
   Abstract »    Full Text »    PDF »
Identification of a Ras Palmitoyltransferase in Saccharomyces cerevisiae.
S. Lobo, W. K. Greentree, M. E. Linder, and R. J. Deschenes (2002)
J. Biol. Chem. 277, 41268-41273
   Abstract »    Full Text »    PDF »
Megalin Functions as an Endocytic Sonic Hedgehog Receptor.
R. A. McCarthy, J. L. Barth, M. R. Chintalapudi, C. Knaak, and W. S. Argraves (2002)
J. Biol. Chem. 277, 25660-25667
   Abstract »    Full Text »    PDF »
Drosophila Segment Polarity Gene Product Porcupine Stimulates the Posttranslational N-Glycosylation of Wingless in the Endoplasmic Reticulum.
K. Tanaka, Y. Kitagawa, and T. Kadowaki (2002)
J. Biol. Chem. 277, 12816-12823
   Abstract »    Full Text »    PDF »
Distance-dependent cellular palmitoylation of de-novo-designed sequences and their translocation to plasma membrane subdomains.
I. Navarro-Lerida, A. Alvarez-Barrientos, F. Gavilanes, and I. Rodriguez-Crespo (2002)
J. Cell Sci. 115, 3119-3130
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)