Lipids Link Membrane Molecules

Science Signaling  08 Dec 2009:
Vol. 2, Issue 100, pp. ec390
DOI: 10.1126/scisignal.2100ec390

Binding of the Hedgehog (Hh) ligand to its receptor Patched (Ptc) relieves Ptc repression of Smoothened (Smo), a seven-transmembrane protein that transduces the Hh signal by promoting the nuclear translocation of the transcription factor Cubitus interruptus (Ci) while preventing processing of full-length Ci into its truncated, repressor form. Ptc represses Smo indirectly by promoting its removal from the plasma membrane and subsequent degradation. Exactly how Ptc represses Smo activity is not known, although it is hypothesized that lipid trafficking may play a role. Khaliullina et al. investigated the relationship between Smo regulation and Lipophorin (Lpp), a lipoprotein particle with which Hh associates and that is required for normal Hh activity, in the fruit fly Drosophila melanogaster. In wing discs in which Lpp was reduced by RNA interference (RNAi) directed against the protein components of this lipoprotein particle, Smo accumulated in the basolateral plasma membrane and Ci processing was blocked in cells in which Ptc normally represses Smo activity. Culturing these Lpp RNAi wing discs with lipids purified from Lpp particles reversed Smo membrane accumulation but could not reverse Smo membrane accumulation in clones of cells that either lacked Ptc or carried only a mutant form of Ptc in which the sterol-sensing domain (SSD) was not functional (PtcSSD). The Ptc SSD was required for sterols to exit endosomes, suggesting that Ptc mobilizes the lipid component of the Lpp particles. Overexpression of a transgene encoding Ptc slowed Lpp degradation and caused Lpp to accumulate and colocalize with Ptc in early endosomes. This Lpp endosomal accumulation did not require the presence of Hh or the Ptc SSD but did require internalization of Ptc. Overexpression of a transgene encoding PtcSSD caused Smo to accumulate in endosomes with PtcSSD and Lpp, whereas trafficking of other basolateral membrane proteins was unaffected. The authors propose that Ptc, the SSD of which is required both for lipid and Smo trafficking from endosomes, modulates the lipid composition of endosomes, which in turn affects the balance between Smo degradation and recycling as it passes through endosomes.

H. Khaliullina, D. Panáková, C. Eugster, F. Riedel, M. Carvalho, S. Eaton, Patched regulates Smoothened trafficking using lipoprotein-derived lipids. Development 136, 4111–4121 (2009). [PubMed]