MAEA is an E3 ubiquitin ligase promoting autophagy and maintenance of haematopoietic stem cells

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.

Vector competence and immune response of Aedes aegypti for Ebinur Lake virus, a newly classified mosquito-borne orthobunyavirus

“…Several immune-related genes have been identified in EBIV-infected Ae . aegypti , such as E3 ubiquitin ligase related to autophagy [ 53 ], zinc finger protein 37 homolog isoform X1/X2 (a transcription factor) and beta-galactoside-binding lectin-like involved in the process of virus infection [ 54 ] ( Fig 4A ). Moreover, five zinc-finger protein-encoding genes showed differential expression patterns ( gene-LOC110680747 , gene-LOC5571062 , gene-LOC5576563 and gene-LOC110680309 were downregulated while gene-LOC5573104 was upregulated) ( S4 Table ).…”

Evolution of severe (transfusion‐dependent) anaemia in myelodysplastic syndromes with 5q deletion is characterized by a macrophage‐associated failure of the eythropoietic niche

“…Considering the relevance of marrow macrophages [44][45][46][47][48] and their adhesion to NEC 49,50 to an adequate function of erythropoiesis, [51][52][53][54] a macrophage-associated alteration of the erythropoietic niche, hindering its compensatory increase as well as markedly reducing the overall productive capacity of erythropoiesis, appears to be the leading factor of aggravation of anaemia in MDS.del(5q). The macrophageassociated loss of Ery-Is may furthermore predict reduced efficacy of lenalidomide, the standard therapy of MDS.…”

Identification of Regulatory Factors and Prognostic Markers in Amyotrophic Lateral Sclerosis

“…MAEA is also an agonist of cannabinoid receptor 1 (CB1), which mediates macrophage phagocytosis [ 99 ]. MAEA is a membrane-associated E3 ubiquitin ligase subunit that is essential for the maintenance of hematopoietic stem cells and lymphatic potential; deletion of MAEA increases the expression of surface cytokine receptors in hematopoietic stem cells and impairs autophagy flux [ 100 ]. MAEA overexpression in primary mouse liver cells attenuates hepatic gluconeogenesis and reduces the risk of insulin resistance, which may improve type 2 diabetes mellitus [ 101 , 102 ].…”