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Mutation of kri1l causes definitive hematopoiesis failure via PERK-dependent excessive autophagy induction
文献类型：期刊论文
| 作者 | Jia, XE; Ma, K; Xu, T; Gao, L; Wu, S; Fu, C; Zhang, WJ; Wang, ZZ; Liu, KY; Dong, M |
| 刊名 | CELL RESEARCH
 |
| 出版日期 | 2015 |
| 卷号 | 25期号:8页码:946-962 |
| 关键词 | UNFOLDED PROTEIN RESPONSE DIAMOND-BLACKFAN ANEMIA BCL-X-L STEM-CELLS EMBRYONIC-DEVELOPMENT ZEBRAFISH DEVELOPMENT MONITORING AUTOPHAGY RIBOSOME BIOGENESIS ERYTHROID-CELLS QUALITY CONTROL |
| 通讯作者 | Pan, WJ (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Key Lab Stem Cell Biol, Shanghai, Peoples R China.,yzhou@enders.tch.harvard.edu |
| 英文摘要 | 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. |
| WOS标题词 | Cell Biology |
| 学科主题 | Cell Biology |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000358941100008 |
| 公开日期 | 2016-02-26 |
| 源URL | [http://ir.sibs.ac.cn/handle/331001/3938]  |
| 专题 | 上海神经科学研究所_神经所(总) |
| 推荐引用方式 GB/T 7714 | Jia, XE,Ma, K,Xu, T,et al. Mutation of kri1l causes definitive hematopoiesis failure via PERK-dependent excessive autophagy induction[J]. CELL RESEARCH,2015,25(8):946-962. |
| APA | Jia, XE.,Ma, K.,Xu, T.,Gao, L.,Wu, S.,...&Pan, WJ.(2015).Mutation of kri1l causes definitive hematopoiesis failure via PERK-dependent excessive autophagy induction.CELL RESEARCH,25(8),946-962. |
| MLA | Jia, XE,et al."Mutation of kri1l causes definitive hematopoiesis failure via PERK-dependent excessive autophagy induction".CELL RESEARCH 25.8(2015):946-962. |
入库方式： OAI收割
来源：上海神经科学研究所
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