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

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  • Qiaozhi Wei

    (Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
    Albert Einstein College of Medicine
    Regeneron Pharmaceuticals, Inc.)

  • Sandra Pinho

    (Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    University of Illinois at Chicago)

  • Shuxian Dong

    (Albert Einstein College of Medicine)

  • Halley Pierce

    (Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
    Albert Einstein College of Medicine)

  • Huihui Li

    (Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
    Albert Einstein College of Medicine)

  • Fumio Nakahara

    (Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
    Albert Einstein College of Medicine
    The University of Tokyo)

  • Jianing Xu

    (Memorial Sloan Kettering Cancer Center)

  • Chunliang Xu

    (Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
    Albert Einstein College of Medicine)

  • Philip E. Boulais

    (Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
    Albert Einstein College of Medicine)

  • Dachuan Zhang

    (Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
    Albert Einstein College of Medicine)

  • Maria Maryanovich

    (Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
    Albert Einstein College of Medicine)

  • Ana Maria Cuervo

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine
    Institute for Aging Studies, Albert Einstein College of Medicine)

  • Paul S. Frenette

    (Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research
    Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

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.

Suggested Citation

  • 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 & Paul S. , 2021. "MAEA is an E3 ubiquitin ligase promoting autophagy and maintenance of haematopoietic stem cells," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22749-1
    DOI: 10.1038/s41467-021-22749-1
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    Cited by:

    1. Shuai Qiao & Chia-Wei Lee & Dawafuti Sherpa & Jakub Chrustowicz & Jingdong Cheng & Maximilian Duennebacke & Barbara Steigenberger & Ozge Karayel & Duc Tung Vu & Susanne Gronau & Matthias Mann & Floria, 2022. "Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Nelson V. Simwela & Luana Johnston & Paulina Pavinski Bitar & Eleni Jaecklein & Craig Altier & Christopher M. Sassetti & David G. Russell, 2024. "Genome-wide screen of Mycobacterium tuberculosis-infected macrophages revealed GID/CTLH complex-mediated modulation of bacterial growth," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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