Arih2 regulates Hedgehog signaling through smoothened ubiquitylation and ER-associated degradation.
J Cell Sci
; 135(16)2022 08 15.
Article
em En
| MEDLINE
| ID: mdl-35899529
ABSTRACT
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 Arih2α found primarily in the nucleus and Arih2ß found on the cytoplasmic face of the endoplasmic reticulum (ER). Re-expression of ER-localized Arih2ß but not nuclear-localized Arih2α rescues the Arih2 mutant phenotypes. When Arih2 is defective, protein aggregates accumulate in the ER and the unfolded protein response is activated. Arih2ß 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ubiquitina-Proteína Ligases
/
Proteínas Hedgehog
/
Degradação Associada com o Retículo Endoplasmático
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
J Cell Sci
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos