Role of lipid metabolism in smoothened derepression in hedgehog signaling.
The binding of Hedgehog (Hh) to its receptor Patched causes derepression of Smoothened (Smo), resulting in the activation of the Hh pathway. Here, we show that Smo activation is dependent on the levels of the phospholipid phosphatidylinositol-4 phosphate (PI4P). Loss of STT4 kinase, which is required for the generation of PI4P, exhibits hh loss-of-function phenotypes, whereas loss of Sac1 phosphatase, which is required for the degradation of PI4P, results in hh gain-of-function phenotypes in multiple settings during Drosophila development. Furthermore, loss of Ptc function, which results in the activation of Hh pathway, also causes an increase in PI4P levels. Sac1 functions downstream of STT4 and Ptc in the regulation of Smo membrane localization and Hh pathway activation. Taken together, our results suggest a model in which Ptc directly or indirectly functions to suppress the accumulation of PI4P. Binding of Hh to Ptc derepresses the levels of PI4P, which, in turn, promotes Smo activation.
Yavari
Amir
A
Department of Molecular, Cell, and Developmental Biology, Department of Biological Chemistry, Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
Nagaraj
Raghavendra
R
Owusu-Ansah
Edward
E
Folick
Andrew
A
Ngo
Kathy
K
Hillman
Tyler
T
Call
Gerald
G
Rohatgi
Rajat
R
Scott
Matthew P
MP
Banerjee
Utpal
U
D019870:1-Phosphatidylinositol 4-Kinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D053148:Caspase 3 / Q000378:metabolism; D004330:Drosophila / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D005123:Eye / Q000254:growth & development / Q000378:metabolism; D017344:Genes, Insect; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D050356:Lipid Metabolism; D009154:Mutation; D010641:Phenotype; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D051155:Wnt1 Protein / Q000378:metabolism
D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D018129:Phosphatidylinositol Phosphates; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; D051155:Wnt1 Protein; C064196:dpp protein, Drosophila; C037178:phosphatidylinositol 4-phosphate; C070844:ptc protein, Drosophila; C100664:smo protein, Drosophila; C074622:wg protein, Drosophila; C077245:hh protein, Drosophila; D019870:1-Phosphatidylinositol 4-Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D053148:Caspase 3