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

Qiaozhi Wei, Sandra Pinho, Shuxian Dong, Halley Pierce, Huihui Li, Fumio Nakahara, Jianing Xu, Chunliang Xu, Philip E. Boulais, Dachuan Zhang, Maria Maryanovich, Ana Maria Cuervo and Paul S. Frenette ()
Additional contact information
Qiaozhi Wei: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
Sandra Pinho: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
Shuxian Dong: Albert Einstein College of Medicine
Halley Pierce: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
Huihui Li: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
Fumio Nakahara: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
Jianing Xu: Memorial Sloan Kettering Cancer Center
Chunliang Xu: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
Philip E. Boulais: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
Dachuan Zhang: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
Maria Maryanovich: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
Ana Maria Cuervo: Albert Einstein College of Medicine
Paul S. Frenette: Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22749-1

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