The Hedgehog (Hh) signaling pathway controls main steps in development and cellular homeostasis. At the plasma membrane, the Hh signal is relayed into the cell through the Patched (Ptc) receptor and the transducer Smoothened (Smo), leading to Hh target gene expression. Accumulation of Smo at the cell surface is inhibited by endocytosis, which leads to Smo activation. However, whether Smo can be activated inside the cell and any potential mechanism for intracellular Smo activation are unknown. In this issue, Jianhang Jia and colleagues describe the discovery of an intracellular activation of Smo that is independent of Hh and Ptc (jcs211367). The authors inactivate intracellular trafficking components of the endosomal sorting complex required for transport III (ESCRT-III) pathway that is upstream of lysosome-mediated degradation, and observe strong accumulation of both active and inactive forms of Smo and, consequently, active downstream signaling of Hh. Upon interruption of endosomal intracellular signaling through ESCRTs 0, I and II, only weak accumulation of Smo is seen. Importantly, the authors find that this is owing to a pathway functioning in parallel to endocytosis; it is mediated by the Drosophila β-arrestin2, Krz, to direct Smo towards ESCRT-III and lysosomal degradation. These results establish a new model for intracellular activation of Smo through contribution of different pathways and point towards a role of this intracellular Smo overaccumulation in the strong tissue overgrowth that is observed upon Smo mis-regulation.
