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

1. Nat Commun. 2023 Apr 21;14(1):2290. doi: 10.1038/s41467-023-38001-x.

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

Herrejon Chavez F(#)(1)(2), Luo H(1), Cifani P(1)(3), Pine A(4), Chu EL(1)(5), Joshi S(6), Barin E(1)(6)(7), Schurer A(1), Chan M(1), Chang K(1), Han GYQ(1), Pierson AJ(1), Xiao M(8), Yang X(1), Kuehm LM(9), Hong Y(10), Nguyen DTT(1)(11), Chiosis G(6), Kentsis A(1)(12)(13), Leslie C(4), Vu LP(#)(14)(15)(16), Kharas MG(17).

Author information: (1)Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2)Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3)Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. (4)Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5)Department of Pharmacology, Weill Cornell School of Medical Sciences, New York, NY, USA. (6)Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7)Pharmacology Program of the Weill Cornell Graduate School of Medicine Sciences, New York, NY, USA. (8)Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA. (9)Cell Microsystems, Inc., Durham, NC, USA. (10)Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, 3086, Australia. (11)Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. (12)Tow Center for Developmental Oncology, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13)Departments of Pediatrics, Pharmacology, and Physiology & Biophysics, Weill Medical College of Cornell University, New York, NY, USA. (14)Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. lvu@bccrc.ca. (15)Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, BC, Canada. lvu@bccrc.ca. (16)Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada. lvu@bccrc.ca. (17)Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. kharasm@mskcc.org. (#)Contributed equally

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.

© 2023. The Author(s).

DOI: 10.1038/s41467-023-38001-x PMCID: PMC10121618 PMID: 37085479 [Indexed for MEDLINE]

Conflict of interest statement: A.K. is a consultant to Rgenta, Novartis, and Blueprint Medicines. M.G.K. is a SAB member of 858 Therapeutics and received honorarium from Kumquat, AstraZeneca and Consultancy with Transition Bio. The remaining authors declare no competing interests.