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

J Exp Med. 2015 Apr 6;212(4):525-38. doi: 10.1084/jem.20141438. Epub 2015 Mar 30.


The status of long-term quiescence and dormancy guarantees the integrity of hematopoietic stem cells (HSCs) during adult homeostasis. However the molecular mechanisms regulating HSC dormancy remain poorly understood. Here we show that cylindromatosis (CYLD), a tumor suppressor gene and negative regulator of NF-κB signaling with deubiquitinase activity, is highly expressed in label-retaining dormant HSCs (dHSCs). Moreover, Cre-mediated conditional elimination of the catalytic domain of CYLD induced dHSCs to exit quiescence and abrogated their repopulation and self-renewal potential. This phenotype is dependent on the interactions between CYLD and its substrate TRAF2 (tumor necrosis factor-associated factor 2). HSCs expressing a mutant CYLD with an intact catalytic domain, but unable to bind TRAF2, showed the same HSC phenotype. Unexpectedly, the robust cycling of HSCs lacking functional CYLD-TRAF2 interactions was not elicited by increased NF-κB signaling, but instead by increased activation of the p38MAPK pathway. Pharmacological inhibition of p38MAPK rescued the phenotype of CYLD loss, identifying the CYLD-TRAF2-p38MAPK pathway as a novel important regulator of HSC function restricting HSC cycling and promoting dormancy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / immunology*
  • Deubiquitinating Enzyme CYLD
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / immunology*
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / immunology*
  • Mice
  • Mice, Knockout
  • Mutation
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • TNF Receptor-Associated Factor 2 / genetics
  • TNF Receptor-Associated Factor 2 / immunology*
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / immunology*


  • NF-kappa B
  • TNF Receptor-Associated Factor 2
  • p38 Mitogen-Activated Protein Kinases
  • CYLD protein, mouse
  • Deubiquitinating Enzyme CYLD
  • Cysteine Endopeptidases