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

Xiao E. Jia, Ke Ma, Tao Xu, Lei Gao, Shuang Wu, Cong Fu, Wenjuan Zhang, Zhizhang Wang, Kaiyu Liu, Mei Dong, Changbin Jing, Chunguang Ren, Zhiwei Dong, Yi Chen, Yi Jin, Qiuhua Huang, Xing Chang, Min Deng, Li Li, Lingfei LuoJun Zhu, Yongjun Dang, Hung Chun Chang, Leonard I. Zon, Yi Zhou, Saijuan Chen, Weijun Pan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)946-962
Number of pages17
JournalCell Research
Volume25
Issue number8
DOIs
StatePublished - Aug 6 2015

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Keywords

  • Hematopoietic stem cells
  • PERK
  • autophagy
  • kri1l
  • misfolded/unfolded protein
  • ribosome biogenesis
  • zebrafish

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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., ... Pan, W. (2015). Mutation of kri1l causes definitive hematopoiesis failure via PERK-dependent excessive autophagy induction. Cell Research, 25(8), 946-962. https://doi.org/10.1038/cr.2015.81