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Mutation of kri1l causes ribosomopathy-like hematopoiesis failure via excessive autophagy

Xiao-E Jia  Ke Ma  Tao Xu  Changbin Jing  Lei Gao  Cong Fu  Wenjuan Zhang  Shuang Wu  Mei Dong  Chunguang Ren  Yi Chen  Yi Jin  Min Deng  Li Li  Lingfei Luo  Jun Zhu  Leonard I.Zon  Yi Zhou  Saijuan Chen  Weijun Pan  
【摘要】:Dysregulation of ribosome biogenesis called ribosomopathies causes human diseases,such as Diamond-Blackfan anemia(DBA)or 5q minus(5q-)syndrome.The mechanism of blood disorder in these diseases remains elusive.Through genetic cloning and mechanism characterization of zebrafish mutant~(cas002),we report a novel connection between ribosomal dysfunction and excessive autophagy in regulation of hematopoietic stem and progenitor cells(HSPCs).This mutant carries a recessive lethal mutation in kril1 gene that encodes an essential component of rRNA small subunit processome.We showed that Krill function was required for normal ribosome biogenesis,expansion of definitive HSPCs and subsequent lineage differentiation.Overexpression of Bcl2,but not p53 inhibition,could fully rescue hematopoietic defects in krill~(cas002)mutants.This rescue is distinguished from cell apoptosis regulated by p53 in other ribosomopathies.Through live imaging and biochemical studies,we found loss of Kri11 function induced excessive autophagy in HSPCs.Treatment with autophagy inhibitors(3-MA,Baf A1)markedly restored HSPCs function and recovered hematopoietic lineages in krill~(cas002)mutants.Inhibition of autophagy may provide clinical benefits to anemic or ribosomopathy patients with increased autophagy in HSPCs.

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