PUBLICATION
Lysosomal membrane protein TMEM106B modulates hematopoietic stem and progenitor cell proliferation and differentiation by regulating LAMP2A stability
- Authors
- Guo, D., Xiong, H., Yang, Z., Zhang, R., Shi, P., Yao, Y., Liu, M., Xu, C., Wang, Q.K.
- ID
- ZDB-PUB-240810-1
- Date
- 2024
- Source
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology 38: e23870e23870 (Journal)
- Registered Authors
- Liu, Mugen, Wang, Qing
- Keywords
- LAMP2A, TMEM106B, hematopoiesis, hematopoietic stem and progenitor cells (HSPCs), hematopoietic stem cells (HSCs), zebrafish
- MeSH Terms
-
- Hematopoiesis/physiology
- Cell Proliferation*
- Cell Differentiation*
- Hematopoietic Stem Cells*/cytology
- Hematopoietic Stem Cells*/metabolism
- Zebrafish*
- Lysosomes/metabolism
- Animals
- Humans
- Lysosomal-Associated Membrane Protein 2*/genetics
- Lysosomal-Associated Membrane Protein 2*/metabolism
- Membrane Proteins*/genetics
- Membrane Proteins*/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 39120151 Full text @ FASEB J.
Citation
Guo, D., Xiong, H., Yang, Z., Zhang, R., Shi, P., Yao, Y., Liu, M., Xu, C., Wang, Q.K. (2024) Lysosomal membrane protein TMEM106B modulates hematopoietic stem and progenitor cell proliferation and differentiation by regulating LAMP2A stability. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 38:e23870e23870.
Abstract
Hematopoietic stem and progenitor cells (HSPCs) are successfully employed for hematological transplantations, and impaired HSPC function causes hematological diseases and aging. HSPCs maintain the lifelong homeostasis of blood and immune cells through continuous self-renewal and maintenance of the multilineage differentiation potential. TMEM106B is a transmembrane protein localized on lysosomal membranes and associated with neurodegenerative and cardiovascular diseases; however, its roles in HSPCs and hematopoiesis are unknown. Here, we established tmem106bb-/- knockout (KO) zebrafish and showed that tmem106bb KO reduced the proliferation of HSPCs during definitive hematopoiesis. The differentiation potential of HSPCs to lymphoid lineage was reduced, whereas the myeloid and erythroid differentiation potentials of HPSCs were increased in tmem106bb-/- zebrafish. Similar results were obtained with morpholino knockdown of tmem106bb. Mechanistically, TMEM106B interacted with LAMP2A, the lysosomal associated membrane protein 2A, impaired LAMP2A-Cathepsin A interaction, and enhanced LAMP2A stability; tmem106bb KO or TMEM106B knockdown caused LAMP2A degradation and impairment of chaperone-mediated autophagy (CMA). Knockdown of lamp2a caused similar phenotypes to that in tmem106bb-/- zebrafish, and overexpression of lamp2a rescued the impaired phenotypes of HSPCs in tmem106bb-/- embryos. These results uncover a novel molecular mechanism for the maintenance of HSPC proliferation and differentiation through stabilizing LAMP2A via TMEM106B-LAMP2A interaction.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping