Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway

Area of Science:

• Hematology
• Stem Cell Biology
• Molecular Oncology

Background:

• Hematopoietic stem cells (HSCs) maintain adult homeostasis through long-term quiescence and dormancy.
• The molecular mechanisms governing HSC dormancy are not fully understood.
• Cylindromatosis (CYLD) is a tumor suppressor gene with deubiquitinase activity, known to negatively regulate NF-κB signaling.

Purpose of the Study:

• To investigate the role of CYLD in regulating HSC dormancy.
• To elucidate the molecular pathways involved in CYLD-mediated HSC function.

Main Methods:

• Conditional gene deletion of CYLD's catalytic domain in HSCs.
• Analysis of HSC dormancy, repopulation, and self-renewal potential.
• Investigation of CYLD interactions with TRAF2 (tumor necrosis factor-associated factor 2).
• Assessment of NF-κB and p38MAPK pathway activation.

Main Results:

• CYLD is highly expressed in dormant HSCs (dHSCs).
• Elimination of CYLD's catalytic activity or its interaction with TRAF2 induced dHSCs to exit quiescence, impairing their function.
• HSC cycling was driven by p38MAPK pathway activation, not NF-κB, upon loss of CYLD-TRAF2 interaction.
• Pharmacological inhibition of p38MAPK rescued the phenotype.

Conclusions:

• The CYLD-TRAF2-p38MAPK pathway is a novel regulator of HSC function.
• This pathway restricts HSC cycling and promotes dormancy, ensuring HSC integrity.
• CYLD plays a critical role in maintaining HSC quiescence and self-renewal capacity.