The CKS1/CKS2 Proteostasis Axis Is Crucial to Maintain Hematopoietic Stem Cell Function

William Grey; Samantha Atkinson; Beatrice Rix; Pedro Casado; Linda Ariza-McNaughton; Cathy Hawley; Miriam L Sopoena; Katherine S Bridge; David Kent; Pedro R Cutillas; Dominique Bonnet

doi:10.1097/HS9.0000000000000853

The CKS1/CKS2 Proteostasis Axis Is Crucial to Maintain Hematopoietic Stem Cell Function

William Grey, Samantha Atkinson, Beatrice Rix, Pedro Casado, Linda Ariza-McNaughton, Cathy Hawley, Miriam L Sopoena, Katherine S Bridge, David Kent, Pedro R Cutillas, Dominique Bonnet

Research output: Contribution to journal › Article › peer-review

Abstract

Long-term hematopoietic stem cells are rare, highly quiescent stem cells of the hematopoietic system with life-long self-renewal potential and the ability to transplant and reconstitute the entire hematopoietic system of conditioned recipients. Most of our understanding of these rare cells has relied on cell surface identification, epigenetic, and transcriptomic analyses. Our knowledge of protein synthesis, folding, modification, and degradation-broadly termed protein homeostasis or "proteostasis"-in these cells is still in its infancy, with very little known about how the functional state of the proteome is maintained in hematopoietic stem cells. We investigated the requirement of the small phospho-binding adaptor proteins, the cyclin-dependent kinase subunits (CKS1 and CKS2), for maintaining ordered hematopoiesis and long-term hematopoietic stem cell reconstitution. CKS1 and CKS2 are best known for their roles in p27 degradation and cell cycle regulation, and by studying the transcriptome and proteome of Cks1 -/- and Cks2 -/- mice, we demonstrate regulation of key signaling pathways that govern hematopoietic stem cell biology including AKT, FOXO1, and NFκB, together balancing protein homeostasis and restraining reactive oxygen species to ensure healthy hematopoietic stem cell function.

Original language	English
Article number	e853
Number of pages	12
Journal	HemaSphere
Volume	7
Issue number	3
DOIs	https://doi.org/10.1097/HS9.0000000000000853
Publication status	Published - Mar 2023

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title = "The CKS1/CKS2 Proteostasis Axis Is Crucial to Maintain Hematopoietic Stem Cell Function",

abstract = "Long-term hematopoietic stem cells are rare, highly quiescent stem cells of the hematopoietic system with life-long self-renewal potential and the ability to transplant and reconstitute the entire hematopoietic system of conditioned recipients. Most of our understanding of these rare cells has relied on cell surface identification, epigenetic, and transcriptomic analyses. Our knowledge of protein synthesis, folding, modification, and degradation-broadly termed protein homeostasis or {"}proteostasis{"}-in these cells is still in its infancy, with very little known about how the functional state of the proteome is maintained in hematopoietic stem cells. We investigated the requirement of the small phospho-binding adaptor proteins, the cyclin-dependent kinase subunits (CKS1 and CKS2), for maintaining ordered hematopoiesis and long-term hematopoietic stem cell reconstitution. CKS1 and CKS2 are best known for their roles in p27 degradation and cell cycle regulation, and by studying the transcriptome and proteome of Cks1 -/- and Cks2 -/- mice, we demonstrate regulation of key signaling pathways that govern hematopoietic stem cell biology including AKT, FOXO1, and NFκB, together balancing protein homeostasis and restraining reactive oxygen species to ensure healthy hematopoietic stem cell function. ",

author = "William Grey and Samantha Atkinson and Beatrice Rix and Pedro Casado and Linda Ariza-McNaughton and Cathy Hawley and Sopoena, {Miriam L} and Bridge, {Katherine S} and David Kent and Cutillas, {Pedro R} and Dominique Bonnet",

note = "Copyright {\textcopyright} 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.",

year = "2023",

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AU - Grey, William

AU - Atkinson, Samantha

AU - Rix, Beatrice

AU - Casado, Pedro

AU - Ariza-McNaughton, Linda

AU - Hawley, Cathy

AU - Sopoena, Miriam L

AU - Bridge, Katherine S

AU - Kent, David

AU - Cutillas, Pedro R

AU - Bonnet, Dominique

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N2 - Long-term hematopoietic stem cells are rare, highly quiescent stem cells of the hematopoietic system with life-long self-renewal potential and the ability to transplant and reconstitute the entire hematopoietic system of conditioned recipients. Most of our understanding of these rare cells has relied on cell surface identification, epigenetic, and transcriptomic analyses. Our knowledge of protein synthesis, folding, modification, and degradation-broadly termed protein homeostasis or "proteostasis"-in these cells is still in its infancy, with very little known about how the functional state of the proteome is maintained in hematopoietic stem cells. We investigated the requirement of the small phospho-binding adaptor proteins, the cyclin-dependent kinase subunits (CKS1 and CKS2), for maintaining ordered hematopoiesis and long-term hematopoietic stem cell reconstitution. CKS1 and CKS2 are best known for their roles in p27 degradation and cell cycle regulation, and by studying the transcriptome and proteome of Cks1 -/- and Cks2 -/- mice, we demonstrate regulation of key signaling pathways that govern hematopoietic stem cell biology including AKT, FOXO1, and NFκB, together balancing protein homeostasis and restraining reactive oxygen species to ensure healthy hematopoietic stem cell function.

AB - Long-term hematopoietic stem cells are rare, highly quiescent stem cells of the hematopoietic system with life-long self-renewal potential and the ability to transplant and reconstitute the entire hematopoietic system of conditioned recipients. Most of our understanding of these rare cells has relied on cell surface identification, epigenetic, and transcriptomic analyses. Our knowledge of protein synthesis, folding, modification, and degradation-broadly termed protein homeostasis or "proteostasis"-in these cells is still in its infancy, with very little known about how the functional state of the proteome is maintained in hematopoietic stem cells. We investigated the requirement of the small phospho-binding adaptor proteins, the cyclin-dependent kinase subunits (CKS1 and CKS2), for maintaining ordered hematopoiesis and long-term hematopoietic stem cell reconstitution. CKS1 and CKS2 are best known for their roles in p27 degradation and cell cycle regulation, and by studying the transcriptome and proteome of Cks1 -/- and Cks2 -/- mice, we demonstrate regulation of key signaling pathways that govern hematopoietic stem cell biology including AKT, FOXO1, and NFκB, together balancing protein homeostasis and restraining reactive oxygen species to ensure healthy hematopoietic stem cell function.

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