Abstract
Haematopoietic stem cells (HSCs) tightly regulate their quiescence, proliferation, and differentiation to generate blood cells during the entire lifetime. The mechanisms by which these critical activities are balanced are still unclear. Here, we report that Macrophage-Erythroblast Attacher (MAEA, also known as EMP), a receptor thus far only identified in erythroblastic island, is a membrane-associated E3 ubiquitin ligase subunit essential for HSC maintenance and lymphoid potential. Maea is highly expressed in HSCs and its deletion in mice severely impairs HSC quiescence and leads to a lethal myeloproliferative syndrome. Mechanistically, we have found that the surface expression of several haematopoietic cytokine receptors (e.g. MPL, FLT3) is stabilised in the absence of Maea, thereby prolonging their intracellular signalling. This is associated with impaired autophagy flux in HSCs but not in mature haematopoietic cells. Administration of receptor kinase inhibitor or autophagy-inducing compounds rescues the functional defects of Maea-deficient HSCs. Our results suggest that MAEA provides E3 ubiquitin ligase activity, guarding HSC function by restricting cytokine receptor signalling via autophagy.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Autophagosomes / drug effects
-
Autophagosomes / genetics*
-
Autophagosomes / metabolism
-
Autophagosomes / ultrastructure
-
Autophagy / drug effects
-
Autophagy / genetics*
-
Cell Adhesion Molecules / genetics
-
Cell Adhesion Molecules / metabolism*
-
Cytoskeletal Proteins / genetics
-
Cytoskeletal Proteins / metabolism*
-
Gene Expression Profiling
-
Hematopoiesis / drug effects
-
Hematopoiesis / genetics
-
Hematopoietic Stem Cells / drug effects
-
Hematopoietic Stem Cells / metabolism*
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Microscopy, Electron, Transmission
-
Protein Stability
-
Receptors, Thrombopoietin / metabolism
-
Signal Transduction / drug effects
-
Signal Transduction / genetics
-
TOR Serine-Threonine Kinases / metabolism
-
Ubiquitin-Protein Ligases / genetics
-
Ubiquitin-Protein Ligases / metabolism*
-
Ubiquitination
-
fms-Like Tyrosine Kinase 3 / metabolism
Substances
-
Cell Adhesion Molecules
-
Cytoskeletal Proteins
-
Mpl protein, mouse
-
Receptors, Thrombopoietin
-
erythroblast macrophage protein, mouse
-
Ubiquitin-Protein Ligases
-
Flt3 protein, mouse
-
fms-Like Tyrosine Kinase 3
-
TOR Serine-Threonine Kinases