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

Qiaozhi Wei,Jianing Xu,Halley Pierce,Shuxian Dong,Ana Maria Cuervo,Sandra Pinho,Maria Maryanovich,Dachuan Zhang,Huihui Li,Paul S Frenette,Fumio Nakahara,Philip E Boulais,Chunliang Xu

doi:10.1038/s41467-021-22749-1

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.

Highlights

Haematopoietic stem cells (HSCs) tightly regulate their quiescence, proliferation, and differentiation to generate blood cells during the entire lifetime
We found that MaeaCsf1r-Cre HSCs, but not the lymphoid-primed multipotent progenitors (LMPPs), showed reductions in lymphoid differentiation (Fig. 1h)
These results suggest that HSCs in MaeaCsf1r-Cre mice are skewed towards the myeloid lineage at the expense of the lymphoid potential

Summary

Introduction

Haematopoietic stem cells (HSCs) tightly regulate their quiescence, proliferation, and differentiation to generate blood cells during the entire lifetime. 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. Haematopoietic stem cells (HSCs) reside in specialised bone marrow (BM) niches in a metabolically inactive quiescent state with balanced myeloid and lymphoid differentiation potential Both intrinsic and extrinsic mechanisms have been proposed to regulate HSC maintenance and lineage potential[1,2,3]. Maea deletion prolongs receptor surface expression and impairs autophagy flux in HSCs, but not in their mature progeny, providing a mechanism guarding HSC quiescence and function by restricting cytokine receptor signalling and regulating autophagy

Methods

Results

Conclusion