Sel1L-Hrd1 ER-associated degradation maintains ? cell identity via TGF-? signaling.

ABSTRACT: ? Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying ? cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying ? cell-specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while autophagy was necessary for ? cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of ? cell maturation and identity. Using single-cell RNA-Seq, we demonstrated that Sel1L deficiency was not associated with ? cell loss, but rather loss of ? cell identity. Sel1L-Hrd1 ERAD controlled ? cell identity via TGF-? signaling, in part by mediating the degradation of TGF-? receptor 1. Inhibition of TGF-? signaling in Sel1L-deficient ? cells augmented the expression of ? cell maturation markers and increased the total insulin content. Our data revealed distinct pathogenic effects of 2 major proteolytic pathways in ? cells, providing a framework for therapies targeting distinct mechanisms of protein quality control.

SUBMITTER: Shrestha N 

PROVIDER: S-EPMC7324191 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature