The Hedgehog pathway is a signalling cascade that functions through the cilium in vertebrates, and is crucial for proper development and tissue homeostasis. At the basal state, Ptch1 localises to cilia where it inhibits the accumulation of Smo. This inhibition is relieved when a Hedgehog ligands bind Ptch1, causing it to leave the cilium. Gregory Pazour's lab have previously shown that cells lacking the E3 ubiquitin ligase Arih2 accumulate more Smo at cilia when in their basal state than their wild-type counterparts. Overall levels of Smo throughout these cells are also higher. In this study (Lv et al., 2022), they confirm their previous findings and go on to investigate two murine isoforms of Arih2 in greater detail. They demonstrate that Arih2α largely localises to the nucleus whereas Arih2β is found on the cytoplasmic face of the endoplasmic reticulum (ER). Of the two Arih2 isoforms, they show that only Arih2β is able to rescue the Smo phenotypes in Arih2−/− cells, and that this rescue is dependent on its E3 ubiquitin ligase activity. By assaying expression levels of known unfolded protein response (UPR) target genes, they also find that loss of Arih2 leads to ER stress. Together, these findings suggest that Arih2β plays a role in the ER-associated degradation (ERAD) of Smo. The researchers propose a novel pathway for the regulation of global Smo levels, with Arih2β ubiquitylating misfolded or excess Smo to kickstart its proteosome-mediated degradation.
Keeping Smo in check
Keeping Smo in check. J Cell Sci 15 August 2022; 135 (16): e135_e1603. doi:
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