Program in Molecular Medicine, University of Massachusetts Medical School, Biotech II, Suite 213, 373 Plantation Street, Worcester, MA 01605, USA.
Shanghai Key Laboratory of Maternal and Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China200092.
J Cell Sci. 2022 Aug 15;135(16). doi: 10.1242/jcs.260299. Epub 2022 Aug 22.
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 Arih2β found on the cytoplasmic face of the endoplasmic reticulum (ER). Re-expression of ER-localized Arih2β 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. Arih2β 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.
在 Hedgehog 信号通路中，Ptch1 和 Smo 的纤毛水平受到该通路的调节。在基础状态下，Ptch1 定位于纤毛，防止 Smo 的纤毛积累和激活。当结合 Hedgehog 配体时，Ptch1 离开纤毛，解除对 Smo 的抑制。Smo 然后在纤毛中浓缩，被激活并激活下游信号。泛素 E3 连接酶 Arih2 的缺失会增加基础 Hedgehog 信号，增加 Smo 的细胞水平，并增加纤毛 Smo 的基础水平。小鼠表达两种 Arih2 同工型，Arih2α 主要存在于核内，Arih2β 存在于内质网（ER）的细胞质侧。表达 ER 定位的 Arih2β 而不是核定位的 Arih2α 可挽救 Arih2 突变体表型。当 Arih2 缺失时，蛋白质聚集体在 ER 中积累，未折叠蛋白反应被激活。Arih2β 似乎调节 Smo 的 ER 相关降解（ERAD），防止过多的、可能错误折叠的 Smo 到达纤毛并干扰通路调节。
