Drosophila Vps36 is involved in Hh signaling by regulating Smo trafficking

Abstract

Hedgehog (Hh) signaling pathway plays a very important role in metazoan development by controlling pattern formation. Malfunction of Hh signaling pathway leads to numerous serious human diseases, including congenital disorders and cancers. The seven-transmembrane domain protein Smoothened (Smo) is a key transducer of Hh signaling pathway, and mediates the graded Hh signal across the cell plasma membrane, thereby inducing the proper expression of downstream genes. Smo accumulation on cell plasma membrane is regulated by its C-tail phosphorylation and the graded Hh signal. The inhibitory mechanism for Smo membrane accumulation in the absence of Hh, however, is still largely unknown. Here, we report that Vps36 of ESCRT-II complex regulates Smo trafficking between cytosol and plasma membrane by specifically recognizing the ubiquitin signal on Smo in the absence of Hh. Furthermore, in the absence of Hh, Smo is ubiquitinated on its cytoplasmic part, including its internal loops and C-tail. Taken together, our data suggested that ESCRT-II complex, especially Vps36, has a special role in controlling Hh signaling by targeting the membrane protein Smo for its trafficking in the absence of Hh, thereby involving in the regulation of proper Hh signaling activity.