MAEA is an E3 ubiquitin ligase promoting autophagy and maintenance of haematopoietic stem cells
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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 Ma crophage- E rythroblast A ttacher (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.
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HSC maintenance by autophagy is mediated at least in part by MAEA, although it is not yet clear whether this mechanism contributes to HSC ageing.
“HSC maintenance by autophagy is mediated at least in part by a membrane ubiquitin ligase called ‘MAEA’ (macrophage–erythroblast attacher), although it is not yet clear whether this mechanism contributes to HSC ageing107.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [107]
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Ageing and rejuvenation of tissue stem cells and their niches
Brunet, A., Goodell, M. A., & Rando, T. A. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00510-w · Cited by 407 · see citing works
- Authors
- Wei, Q., Pinho, S., Dong, S., Pierce, H., Li, H., Nakahara, F., Xu, J., Xu, C., Boulais, P. E., Zhang, D., Maryanovich, M., Cuervo, A. M., & Frenette, P. S.
- Affiliations
- Albert Einstein College of Medicine (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Frenette, Paul S.
- ORCID
- Venue
- Nature Communications
- Published
- 2021-05-04
- Volume
- 12
- Issue
- 1
- Pages
- 2522-2522
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8097058
- OpenAlex
- W3158677772
- Cited by
- 47
- References
- 55
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 6 · 2023: 14 · 2022: 12 · 2021: 1
- FWCI
- 5.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- New York State Department of Health (NYSTEM IIRP C029570, C029570, C029154)
- Leukemia and Lymphoma Society (LLS-TRP 6475-15)
- New York State Stem Cell Science (C029154, IIRP C029570, C029570)
- National Institutes of Health (C029154, AG031782)
- National Institute on Aging (P01AG031782)
- National Heart, Lung, and Blood Institute (R01HL116340, F32HL142243, R01HL069438)
- National Cancer Institute (P30CA008748)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056638)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- MAEA, EMP, E3 ubiquitin ligase, hematopoietic stem cells, autophagy, HSC quiescence, cytokine receptor signalling, MPL, FLT3, receptor stability, myeloproliferative syndromes
- MeSH terms
- Autophagosomes, Animals, Autophagy, Cytoskeletal Proteins, Hematopoiesis, Hematopoietic Stem Cells, Mice, Inbred C57BL, Signal Transduction, Cell Adhesion Molecules, Mice, Knockout, Gene Expression Profiling, Ubiquitin-Protein Ligases, Microscopy, Electron, Transmission, Mice, fms-Like Tyrosine Kinase 3, Receptors, Thrombopoietin, Ubiquitination, Protein Stability, TOR Serine-Threonine Kinases
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