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Angiogenin Prevents Progranulin A9D Mutation-Induced Neuronal-Like Cell Apoptosis Through Cleaving tRNAs into tiRNAs

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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.

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Acknowledgements

We thank the Core Facilities at Zhejiang University School of Medicine for the technical assistance. This work was supported by grants no. 31570786, no. 81372303 (to Zhengping Xu), no. 81601101 (to Yi Yang), and no. 31400648 (to Jinghao Sheng) from the National Natural Science Foundation of China.

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Authors and Affiliations

  1. Institute of Environmental Health, School of Public Health, Zhejiang University, Hangzhou, 310058, China

    Siqi Li, Yongdui Chen, Desen Sun, Rongpai Bai, Xiangwei Gao, Jinghao Sheng & Zhengping Xu

  2. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, 310058, China

    Rongpai Bai, Jinghao Sheng & Zhengping Xu

  3. Program in Molecular Cell Biology, School of Medicine, Zhejiang University, Hangzhou, 310058, China

    Siqi Li, Desen Sun, Rongpai Bai, Xiangwei Gao, Jinghao Sheng & Zhengping Xu

  4. Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China

    Yi Yang

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  1. Siqi Li
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Li, S., Chen, Y., Sun, D. et al. Angiogenin Prevents Progranulin A9D Mutation-Induced Neuronal-Like Cell Apoptosis Through Cleaving tRNAs into tiRNAs. Mol Neurobiol 55, 1338–1351 (2018). https://doi.org/10.1007/s12035-017-0396-7

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