Cholesterol activates the G-protein coupled receptor Smoothened to promote Hedgehog signaling

Cells must communicate with each other to coordinate the development of most tissues and organs. Damage to these communication systems is often seen in degenerative disorders and in cancer. The Hedgehog signaling pathway is one of a handful of these critical systems. Reduced Hedgehog signals can lead to birth defects, while excessive Hedgehog signals can lead to skin and brain cancers. Cells transmit the Hedgehog signal by releasing a protein into their surroundings, where it can influence neighboring cells. Despite years of study, it is not understood how the Hedgehog signal is transmitted from the outside to the inside of a receiving cell. Studies first done in flies and subsequently confirmed in humans have shown that a protein called Smoothened is needed to transmit the Hedgehog signal across the membrane of receiving cells. But it was not known how Smoothened carries out this critical signaling step to influence gene activation inside the cell and consequently to change cell behavior. Now, Luchetti, Sircar et al. find that cholesterol, an important component of the cell membrane, directly binds to Smoothened and changes its shape so that it can activate Hedgehog signaling components inside cells. The experiments made use of mouse cells, and the discovery shows that cholesterol may play a previously underappreciated role in cell-to-cell communication. This newly discovered role for cholesterol has implications for diseases, including a unique set of developmental disorders caused by abnormalities in pathways that produce cholesterol in human cells. Furthermore, this unexpected insight into Smoothened’s activity may be clinically important, because Smoothened can cause cancer when mutated and is the target of anti-cancer drugs that are being used in the clinic. Following on from these findings, a major step will be to uncover if and how Hedgehog signals regulate cholesterol to allow Smoothened to transmit these signals across the cell membrane.