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

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, Michael Xiao, Xuejing Yang, Lindsey M. Kuehm, Yuning Hong, Diu T. T. Nguyen, Gabriela Chiosis, Alex Kentsis, Christina Leslie, Ly P. Vu () and Michael G. Kharas ()
Additional contact information
Florisela Herrejon Chavez: Memorial Sloan Kettering Cancer Center
Hanzhi Luo: Memorial Sloan Kettering Cancer Center
Paolo Cifani: Memorial Sloan Kettering Cancer Center
Alli Pine: Memorial Sloan Kettering Cancer Center
Eren L. Chu: Memorial Sloan Kettering Cancer Center
Suhasini Joshi: Memorial Sloan Kettering Cancer Center
Ersilia Barin: Memorial Sloan Kettering Cancer Center
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
Gabriela Chiosis: Memorial Sloan Kettering Cancer Center
Alex Kentsis: Memorial Sloan Kettering Cancer Center
Christina Leslie: Memorial Sloan Kettering Cancer Center
Ly P. Vu: Memorial Sloan Kettering Cancer Center
Michael G. Kharas: Memorial Sloan Kettering Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38001-x

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