Studies Reveal Regulation of Vps36 on Smo Trafficking

Hedgehog (Hh) signaling plays critical roles in pattern formation and adult tissue homeostasis from insect to human. Malfunction of Hh signaling can lead to birth defects and cancers. The seven transmembrane protein Smoothened (Smo) transduces Hh signals by its plasma membrane-cytosol trafficking. How is Smo trafficking regulated? Scientists from Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences identified that Vps36, a component of ESCRT machinery, specifically regulates Smo trafficking in the absence of Hh.

In a Drosophila wing imaginal discs staining, YANG Xiaofeng, MAO Feifei and their colleagues led by Dr. ZHAO Yun and Dr. ZHANG Lei were surprised to find that knockdown of Vps36 leads to Smo upregulation specifically in the A compartment, where Hh signal is absent. They further performed a series of biochemical assays and characterized that Vps36 could regulate Smo trafficking mainly in the absence of Hh by recognizing the ubiquitin signal on Smo. Further experiments indicate that the ubiquitin signal on Smo is controlled by Hh. According to the experimental results, researchers finally found that all the lysines of Smo in cytoplasmic part, including its internal loops and C-tail, are involved in Smo ubiquitination and trafficking.

These findings indicated that Hh regulates Smo trafficking by control Smo ubiquitination on its cytoplasmic part. Then the ubiquitinated Smo could be further sorted by Vps36 (or ESCRT machinery). Their discoveries provided new insights into the mechanism of Smo trafficking.

This research entitled “Drosophila Vps36 is involved in Hh signaling by regulating Smo trafficking” was published online in the Journal of Cell Science on July 10^th, 2013. It is supported by grants from the National Basic Research Program of China, the National Natural Science Foundation of China, and the “Strategic Priority Research Program” of the Chinese Academy of Sciences.