ERAD Activity Distinguishes the Functional Heterogeneity of Hematopoietic Stem Cells
Peng, Q.; Zheng, M.; Liu, S.; Xie, X.; Shen, Z.; Wang, T.; Liu, H.; Mi, W.; Zhou, J.; Ma, X.; Yin, Z.; Hu, Y.; Shi, G.; Ji, Y.; Zhang, D.; Zheng, J.; Wang, X.; Lv, K.; Li, Q.; Feng, J.; Mei, Y.; Liu, L.
Show abstract
Hematopoietic stem cells (HSCs) rely on precisely controlled proteostasis to sustain lifelong self-renewal, yet whether intrinsic proteostatic characteristics can prospectively define functional diversity within the HSC pool remains unknown. In this study, we developed a dual-fluorescence reporter system to visualize endoplasmic reticulum-associated degradation (ERAD) activity in vivo and discovered that ERAD activity can prospectively predicts the long-term reconstitution potential of HSCs. Remarkably, ERAD states were maintained through self-renewal, revealing an inheritable "proteostatic memory" within the HSC pool. Transcriptomic and functional analyses identified SOCS2 as a key regulator of this process: SOCS2 inhibits JAK2 signaling to sustain ERAD activity, whereas hyperactive JAK2 interacts with the ERAD E3 ligase Hrd1 and suppresses VCP-mediated misfolded substrate. These findings define a SOCS2-JAK2-ERAD axis that connects cytokine signaling to intrinsic proteostasis remodeling, establishing ERAD activity as a predictive and heritable marker of HSC function and providing a conceptual framework for understanding hematopoietic stem cell heterogeneity.
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