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RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells

Author

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  • Florisela Herrejon Chavez

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Hanzhi Luo

    (Memorial Sloan Kettering Cancer Center)

  • Paolo Cifani

    (Memorial Sloan Kettering Cancer Center
    Cold Spring Harbor Laboratory)

  • Alli Pine

    (Memorial Sloan Kettering Cancer Center)

  • Eren L. Chu

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell School of Medical Sciences)

  • Suhasini Joshi

    (Memorial Sloan Kettering Cancer Center)

  • Ersilia Barin

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Pharmacology Program of the Weill Cornell Graduate School of Medicine Sciences)

  • Alexandra Schurer

    (Memorial Sloan Kettering Cancer Center)

  • Mandy Chan

    (Memorial Sloan Kettering Cancer Center)

  • Kathryn Chang

    (Memorial Sloan Kettering Cancer Center)

  • Grace Y. Q. Han

    (Memorial Sloan Kettering Cancer Center)

  • Aspen J. Pierson

    (Memorial Sloan Kettering Cancer Center)

  • Michael Xiao

    (Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program)

  • Xuejing Yang

    (Memorial Sloan Kettering Cancer Center)

  • Lindsey M. Kuehm

    (Cell Microsystems, Inc.)

  • Yuning Hong

    (La Trobe Institute for Molecular Science, La Trobe University)

  • Diu T. T. Nguyen

    (Memorial Sloan Kettering Cancer Center
    Barts Cancer Institute, Queen Mary University of London)

  • Gabriela Chiosis

    (Memorial Sloan Kettering Cancer Center)

  • Alex Kentsis

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Weill Medical College of Cornell University)

  • Christina Leslie

    (Memorial Sloan Kettering Cancer Center)

  • Ly P. Vu

    (Memorial Sloan Kettering Cancer Center
    British Columbia Cancer Research Centre
    University of British Columbia)

  • Michael G. Kharas

    (Memorial Sloan Kettering Cancer Center)

Abstract

Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors. Mechanistically, we find that SYNCRIP loss results in a failure to maintain proteome homeostasis that is essential for HSC maintenance. SYNCRIP depletion results in increased protein synthesis, a dysregulated epichaperome, an accumulation of misfolded proteins and induces endoplasmic reticulum stress. Additionally, we find that SYNCRIP is required for translation of CDC42 RHO-GTPase, and loss of SYNCRIP results in defects in polarity, asymmetric segregation, and dilution of unfolded proteins. Forced expression of CDC42 recovers polarity and in vitro replating activities of HSCs. Taken together, we uncovered a post-transcriptional regulatory program that safeguards HSC self-renewal capacity and blood homeostasis.

Suggested Citation

  • Florisela Herrejon Chavez & Hanzhi Luo & Paolo Cifani & Alli Pine & Eren L. Chu & Suhasini Joshi & Ersilia Barin & Alexandra Schurer & Mandy Chan & Kathryn Chang & Grace Y. Q. Han & Aspen J. Pierson &, 2023. "RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38001-x
    DOI: 10.1038/s41467-023-38001-x
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