GSE133431
MAEA is an E3 ubiquitin ligase promoting autophagy and maintenance of haematopoietic stem cells
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 island1, is a membrane-associated E3 ubiquitin ligase essential for HSC maintenance and lymphoid commitment. Maea is highly expressed in HSCs and its deletion in mice severely impairs HSC quiescence and function and leads to a lethal myeloproliferative syndrome. By contrast, MAEA expression is essential for the development of acute myeloid leukaemia (AML) and up-regulated in human and mouse AML. Mechanistically, we have found that the surface expression of several haematopoietic cytokine receptors (e.g. MPL, FLT3) is stabilised in absence of Maea, thereby prolonging their intracellular signalling. Additionally, the autophagy flux in HSCs, but not in mature haematopoietic cells, is dramatically impaired. Administration of autophagy-inducing compounds rescues the functional defects of Maea-deficient HSCs. These results thus suggest that MAEA is a pivotal E3 ubiquitin ligase guarding HSC function via autophagy. Overall design: mRNA profiles were generated from bone marrow hematopoietic stem cells of 8wk old control and MaeaCsf1r-Cre littermates in triplicates by Illumina NextSeq500 sequencing