Extended Data Fig. 1: SEL1L–ERAD is highly expressed in HSCs compared with progenitors.
a, Diagram showing the ERAD and UPR pathways. The ER is the major subcellular site for synthesis and maturation of all transmembrane and secreted proteins. To maintain protein homeostasis and normal cell function, cells have evolved highly sensitive and sophisticated quality control systems and/or stress response pathways to ensure the fidelity of protein structure. Two such systems conserved across different species are ERAD and UPR. Among the mammalian ERAD complexes, the SEL1L–HRD1 complex, consisting of the E3 ubiquitin ligase HRD1 and its adaptor protein SEL1L, is the most conserved branch that ubiquitinates and targets selective substrates for proteasomal degradation. Many physiological or pathological stresses cause the accumulation of unfolded or misfolded proteins in the ER and activate the ER stress response or UPR that is mediated by three ER transmembrane sensors IRE1α, ATF6 and PERK. IRE1α is the most ancient and conserved sensor of the UPR. Upon activation, IRE1α dimerizes and trans-autophosphorylates to activate its RNase domain to induce unconventional splicing of its substrate XBP1. Recent study reveals that IRE1α, rather than ATF6 and PERK, as a selective endogenous substrate that is degraded by SEL1L–HRD1 ERAD. b, Heatmap showing the expression of ERAD genes in mouse HSCs and progenitors. LT-HSC: long-term HSC (LSK CD150+CD48−CD135−); ST-HSC: short-term HSC (LSK CD150-CD48-CD135-); MPP: multipotent progenitors (LSK CD135+). Data extracted from GSE109125. c, Quantitative RT–PCR analysis of Hrd1 expression in mouse HSCs and progenitors. Data are presented relative to Gapdh. n = 3 biologically independent mice. One-way ANOVA was used to calculate P values. Results are shown as mean ± s.d. Statistical information is provided as source data.
