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.

doi:10.64898/2025.12.01.691501

bioRxiv · 10.64898/2025.12.01.691501

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.

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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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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.. 2025-12-05. ERAD Activity Distinguishes the Functional Heterogeneity of Hematopoietic Stem Cells. https://doi.org/10.64898/2025.12.01.691501

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