PUBLICATION

Mutation of kri1l causes definitive hematopoiesis failure via PERK-dependent excessive autophagy induction

Authors
Jia, X.E., Ma, K., Xu, T., Gao, L., Wu, S., Fu, C., Zhang, W., Wang, Z., Liu, K., Dong, M., Jing, C., Ren, C., Dong, Z., Chen, Y., Jin, Y., Huang, Q., Chang, X., Deng, M., Li, L., Luo, L., Zhu, J., Dang, Y., Chang, H.C., Zon, L.I., Zhou, Y., Chen, S., Pan, W.
ID
ZDB-PUB-150704-3
Date
2015
Source
Cell Research   25(8): 946-62 (Journal)
Registered Authors
Chen, Yi, Deng, Min, Dong, Mei, Dong, Zhiwei, Jing, Chang-Bin, Jin, Yi, Li, Li, Luo, Lingfei, Pan, Weijun, Zhou, Yi, Zon, Leonard I.
Keywords
Hematopoietic stem cells, zebrafish, kri1l, ribosome biogenesis, autophagy, PERK, misfolded/unfolded protein
MeSH Terms
  • Adenine/analogs & derivatives
  • Adenine/pharmacology
  • Animals
  • Autophagy*/genetics
  • Hematopoiesis*/genetics
  • Hematopoietic Stem Cells*/metabolism
  • Hematopoietic Stem Cells*/pathology
  • Indoles/pharmacology
  • Mutation
  • Organelle Biogenesis
  • Protein Kinase Inhibitors/pharmacology
  • Ribosomes/metabolism
  • Zebrafish
  • Zebrafish Proteins/genetics*
  • eIF-2 Kinase/antagonists & inhibitors
  • eIF-2 Kinase/metabolism*
PubMed
26138676 Full text @ Cell Res.
Abstract
Dysregulation of ribosome biogenesis causes human diseases, such as Diamond-Blackfan anemia, del (5q-) syndrome and bone marrow failure. However, the mechanisms of blood disorders in these diseases remain elusive. Through genetic mapping, molecular cloning and mechanism characterization of the zebrafish mutant cas002, we reveal a novel connection between ribosomal dysfunction and excessive autophagy in the regulation of hematopoietic stem/progenitor cells (HSPCs). cas002 carries a recessive lethal mutation in kri1l gene that encodes an essential component of rRNA small subunit processome. We show that Kri1l is required for normal ribosome biogenesis, expansion of definitive HSPCs and subsequent lineage differentiation. Through live imaging and biochemical studies, we find that loss of Kri1l causes the accumulation of misfolded proteins and excessive PERK activation-dependent autophagy in HSPCs. Blocking autophagy but not inhibiting apoptosis by Bcl2 overexpression can fully rescue hematopoietic defects, but not the lethality of kri1l(cas002) embryos. Treatment with autophagy inhibitors (3-MA and Baf A1) or PERK inhibitor (GSK2656157), or knockdown of beclin1 or perk can markedly restore HSPC proliferation and definitive hematopoietic cell differentiation. These results may provide leads for effective therapeutics that benefit patients with anemia or bone marrow failure caused by ribosome disorders.Cell Research advance online publication 3 July 2015; doi:10.1038/cr.2015.81.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping