Jia XE, 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 HC, Zon LI, Zhou Y, Chen S, Pan W. Mutation of kri1l causes definitive hematopoiesis failure via PERK-dependent excessive autophagy induction. Cell Res. 2015 Aug; 25(8):946-62.

Citation

Jia XE, 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 HC, Zon LI, Zhou Y, Chen S, Pan W. 2015. Mutation of kri1l causes definitive hematopoiesis failure via PERK-dependent excessive autophagy induction. Cell research. 25(8):946-62. Pubmed: 26138676 DOI:10.1038/cr.2015.81

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.

Related Faculty

Leonard Zon, M.D.

Zon Lab

The Zon laboratory aims to dissect how assaults to the hematopoietic system cause severe diseases such as leukemias, lymphomas, and anemias. They investigate hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish.