| First Author | Lv B | Year | 2022 |
| Journal | J Cell Sci | Volume | 135 |
| Issue | 16 | PubMed ID | 35899529 |
| Mgi Jnum | J:344145 | Mgi Id | MGI:7572644 |
| Doi | 10.1242/jcs.260299 | Citation | Lv B, et al. (2022) Arih2 regulates Hedgehog signaling through smoothened ubiquitylation and ER-associated degradation. J Cell Sci 135(16) |
| abstractText | During Hedgehog signaling, the ciliary levels of Ptch1 and Smo are regulated by the pathway. At the basal state, Ptch1 localizes to cilia and prevents the ciliary accumulation and activation of Smo. Upon binding a Hedgehog ligand, Ptch1 exits cilia, relieving inhibition of Smo. Smo then concentrates in cilia, becomes activated and activates downstream signaling. Loss of the ubiquitin E3 ligase Arih2 elevates basal Hedgehog signaling, elevates the cellular level of Smo and increases basal levels of ciliary Smo. Mice express two isoforms of Arih2 with Arih2alpha found primarily in the nucleus and Arih2beta found on the cytoplasmic face of the endoplasmic reticulum (ER). Re-expression of ER-localized Arih2beta but not nuclear-localized Arih2alpha rescues the Arih2 mutant phenotypes. When Arih2 is defective, protein aggregates accumulate in the ER and the unfolded protein response is activated. Arih2beta appears to regulate the ER-associated degradation (ERAD) of Smo preventing excess and potentially misfolded Smo from reaching the cilium and interfering with pathway regulation. |
