title: Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway.
abstract: 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.
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.
authors.forename: Melania
authors.initials: M
authors.lastname: Tesio
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany.
authors.forename: Yilang
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Müdder
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Massimo
authors.initials: M
authors.lastname: Saini
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: von Paleske
authors.affiliation: Institut Necker-Enfants Malades (INEM) and Université Paris Sorbonne Cité at Descartes, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1151, Assistance Publique-Hôpitaux de Paris (AP-HP), 75015 Paris, France.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
authors.affiliation: CECAD Research Center, Institute for Genetics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany.
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany The German Cancer Consortium (DKTK), 69120 Heidelberg, Germany a.trumpp@dkfz.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology*; D000074749:Deubiquitinating Enzyme CYLD; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology*
chemical_list: D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D048051:p38 Mitogen-Activated Protein Kinases; C511601:CYLD protein, mouse; D000074749:Deubiquitinating Enzyme CYLD; D003546:Cysteine Endopeptidases
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