The role of lipoprotein association in Hedgehog release, trafficking and signalling
Final Report Abstract
Hedgehog family proteins are secreted signaling molecules that regulate tissue growth and patterning during embryonic development and adult tissue regeneration. As a consequence, mutations affecting the activity of Hedgehog and its signal transduction pathway underlie the development of many different cancers. An understanding of how Hedgehog proteins are secreted, and the mechanisms that regulate their activity is not only a central question in developmental biology, but has important therapeutic implications. We discovered a conserved and central role for lipids and lipoproteins in regulating Hedgehog release and signaling. Because Hedgehog family proteins are covalently attached to cholesterol, they require special mechanisms to release them from cell membranes so that they can spread and signal to other cells. We found that both Drosophila and human Hedgehog proteins can be released on lipoprotein particles, which interact with the sterol moiety. Lipoproteins not only allow Hedgehog proteins to spread, but also contain lipidic signaling molecules that keep the Hedgehog signaling pathway off when Hedgehog isn’t present. When Hedgehog associates with lipoproteins, it prevents their contents from being used to repress the pathway. These findings may help us understand some of the health problems associated with obesity, where lipoprotein levels and metabolism are disturbed. Stem cells in many different organs are regulated by Hedgehog signaling, and we are trying to understand how perturbed lipoprotein metabolism alters Hedgehog signaling, tissue homeostasis and cancer. What are the molecules in lipoproteins that repress Hedgehog signaling? We discovered that they are endocannabinoids – the molecules whose activity is mimicked by the psychoactive phytocannabinoids present in cannabis. Furthermore, we found that phytocannabinoids are themselves potent inhibitors of Hedgehog signaling. Because Hedgehog signaling has important roles in adult tissue homeostasis, this may help explain some of the less well-understood effects of cannabis consumption on human health. Hedgehog proteins don’t normally spread out of the tissue in which they are produced, and are best known for their functions in local tissue patterning. But we also discovered a completely novel role for lipoproteinassociated Hedgehog as an endocrine hormone. Hedgehog that is produced by the Drosophila intestine enters systemic circulation on lipoprotein particles. This pool of Hedgehog signals to the fat body (a tissue that functions as both liver and adipose tissue) as well as to the steroidogenic prothoracic gland to regulate growth, lipid metabolism and developmental timing in response to nutrition. We see a similar pool of Sonic Hedgehog in human and mouse circulation and are investigating whether it might function similarly. While lipoproteins are an important release mechanism for Hedgehog proteins, we have discovered that Hedgehog can also leave the cell in other forms. We found that both Drosophila and human cells produce a novel form of Hedgehog that is missing its sterol anchor. This form of Hedgehog signals differently than lipoprotein-associated Hedgehog. Furthermore, we’ve also discovered other forms of Hedgehog that are covalently modified by important cellular metabolites. Taken together, our work on the cell biology of Hedgehog signaling has uncovered important ways in which organismal metabolism can influence the activity of this critically important pathway. Aspects of this work have been made available to a broader public through a television interview: http://www.3sat.de/page/?source=/scobel/167420/index.html&cx=57 and through an article in the Bildzeitung: http://www.bild.de/regional/dresden/marihuana/hilft-kiffen-gegen-krebs-40229976.bild.html#sthash.uhY9kANY.dpuf
Publications
- (2011). Megalin-dependent yellow endocytosis restricts melanization in the Drosophila cuticle. Development 138, 149-58
Riedel F, Vorkel D, Eaton S.
- (2012) Assembly and Function of Drosophila Lipoproteins. P.L.o.S. Genetics 8(7): e1002828
Palm, W. Sampaio, J. L., Brankatschk, N., Carvalho, M., Mahmoud, A., Shevchenko, A. and Eaton, S.
(See online at https://doi.org/10.1371/journal.pgen.1002828) - Effects of Diet and Development on the Drosophila lipidome. (2012) Molecular Systems Biology 8 Article number: 600
Carvalho, M., Sampaio, J., Palm, W., Brankatschk, M., Eaton, S. and Shevchenko, A.
(See online at https://doi.org/10.1038/msb.2012.29) - (2013) Conserved functions of lipoproteins in secretion and signaling of Hh proteins. P.L.o.S Biol. 11(3): e1001505
Palm, W., Swierczynska, M, Kumari, V., Erhart-Bornstein, M., Bornstein, S., and Eaton, S.
(See online at https://doi.org/10.1371/journal.pbio.1001505) - Production of circulating Hedgehog by the intestine couples nutrition to growth and development. (2014) Genes and Dev. 28:2636-2651
Rodenfels, J., Lavrynenko, O., Ayciriex, S., Sampaio, J., Shevchenko, A. and Eaton, S.
(See online at https://doi.org/10.1101/gad.249763.114) - Lipoproteins carry endocannabinoids that repress the Hedgehog pathway. (2015) Proc. Nat. Acad. Sci. 112: 3415-3420
Khaliullina, H., Sampaio, J., Shevchenko, A. and Eaton, S.
(See online at https://doi.org/10.1101/000570)
