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
  • Humans
  • Cell Proliferation*
  • Cell Differentiation*
  • Lysosomes/metabolism
  • Hematopoiesis/physiology
  • Hematopoietic Stem Cells*/cytology
  • Hematopoietic Stem Cells*/metabolism
  • Membrane Proteins*/genetics
  • Membrane Proteins*/metabolism
  • Lysosomal-Associated Membrane Protein 2*/genetics
  • Lysosomal-Associated Membrane Protein 2*/metabolism
  • Animals
  • Zebrafish*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
(all 15)
PubMed
39120151 Full text @ FASEB J.
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
Figures
Figure Gallery (8 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
la2TgTransgenic Insertion
    zf4012
      		Small Deletion
      1 - 2 of 2
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      Human Disease / Model
      No data available
      Sequence Targeting Reagents
      Target Reagent Reagent Type
      lamp2MO1-lamp2MRPHLNO
      tmem106bbCRISPR1-tmem106bbCRISPR
      tmem106bbMO1-tmem106bbMRPHLNO
      1 - 3 of 3
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      Fish
      No data available
      Antibodies
      No data available
      Orthology
      No data available
      Engineered Foreign Genes
      Marker Marker Type Name
      EGFPEFGEGFP
      1 - 1 of 1
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      Mapping
      No data available
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      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.