title: Angiogenin Prevents Progranulin A9D Mutation-Induced Neuronal-Like Cell Apoptosis Through Cleaving tRNAs into tiRNAs.
abstract: Gene defects have been recognized as prominent factors in the etiology and pathogenesis of neurodegeneration. Among 60 neurodegeneration-related mutations in progranulin (PGRN), a mutation in PGRN gene exon 1 introduces a charged amino acid in the hydrophobic core of its signal peptide at residue 9 (named PGRN A9D) and results in incorrect cytoplasmic sorting. However, the pathogenesis of this mutation remains elusive. To address this issue, we first examined the subcellular distribution of PGRN A9D in human neuronal-like cells (SH-SY5Y). The results showed that PGRN A9D accumulated in cytosolic stress granules. Interestingly, this mis-sorting associated with a cellular redistribution of angiogenin (ANG), a stress-response factor and neurodegenerative disease-related protein, from nucleus to cytoplasmic stress granules, and there existed protein interaction between PGRN A9D and ANG. Further study revealed that the stress granule localization of PGRN A9D was dependent on ANG. Functionally, PGRN A9D abolished the nuclear ANG-mediated biological roles; on the other hand, the relocation of ANG to stress granules activated its cytoprotective stress-response program by cleaving transfer RNAs (tRNAs) to tiRNAs (tRNA-derived, stress-induced small RNAs), thus promoting PGRN A9D cell survival. Taken together, we hypothesize that PGRN A9D leads to the retention of ANG in the cytoplasm to protect cells from PGRN A9D-induced apoptosis, implying that PGRN and ANG act in concert to regulate the progress of neurodegenerative disease.
authors.affiliation: Institute of Environmental Health, School of Public Health, Zhejiang University, Hangzhou, 310058, China.|Program in Molecular Cell Biology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Siqi
authors.initials: S
authors.lastname: Li
authors.affiliation: Institute of Environmental Health, School of Public Health, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Yongdui
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Environmental Health, School of Public Health, Zhejiang University, Hangzhou, 310058, China.|Program in Molecular Cell Biology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Desen
authors.initials: D
authors.lastname: Sun
authors.affiliation: Institute of Environmental Health, School of Public Health, Zhejiang University, Hangzhou, 310058, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, 310058, China.|Program in Molecular Cell Biology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Rongpai
authors.initials: R
authors.lastname: Bai
authors.affiliation: Institute of Environmental Health, School of Public Health, Zhejiang University, Hangzhou, 310058, China.|Program in Molecular Cell Biology, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Gao
authors.affiliation: Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute of Environmental Health, School of Public Health, Zhejiang University, Hangzhou, 310058, China. jhsheng@zju.edu.cn.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, 310058, China. jhsheng@zju.edu.cn.|Program in Molecular Cell Biology, School of Medicine, Zhejiang University, Hangzhou, 310058, China. jhsheng@zju.edu.cn.
authors.forename: Jinghao
authors.initials: J
authors.lastname: Sheng
authors.affiliation: Institute of Environmental Health, School of Public Health, Zhejiang University, Hangzhou, 310058, China. zpxu@zju.edu.cn.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, 310058, China. zpxu@zju.edu.cn.|Program in Molecular Cell Biology, School of Medicine, Zhejiang University, Hangzhou, 310058, China. zpxu@zju.edu.cn.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Xu
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D000077153:Progranulins / Q000235:genetics / Q000378:metabolism*; D012343:RNA, Transfer; D012259:Ribonuclease, Pancreatic / Q000378:metabolism*
chemical_list: D000077153:Progranulins; D012343:RNA, Transfer; C046366:angiogenin; D012259:Ribonuclease, Pancreatic
keywords: Angiogenin; Apoptosis; Neurodegeneration; Progranulin; TiRNA