Letter

A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage

Received:
Accepted:
Published online:

Abstract

Although individuals age and die with time, an animal species can continue indefinitely, because of its immortal germ-cell lineage1. How the germline avoids transmitting damage from one generation to the next remains a fundamental question in biology. Here we identify a lysosomal switch that enhances germline proteostasis before fertilization. We find that Caenorhabditis elegans oocytes whose maturation is arrested by the absence of sperm2 exhibit hallmarks of proteostasis collapse, including protein aggregation. Remarkably, sperm-secreted hormones re-establish oocyte proteostasis once fertilization becomes imminent. Key to this restoration is activation of the vacuolar H+-ATPase (V-ATPase), a proton pump that acidifies lysosomes3. Sperm stimulate V-ATPase activity in oocytes by signalling the degradation of GLD-1, a translational repressor4 that blocks V-ATPase synthesis. Activated lysosomes, in turn, promote a metabolic shift that mobilizes protein aggregates for degradation, and reset proteostasis by enveloping and clearing the aggregates. Lysosome acidification also occurs during Xenopus oocyte maturation; thus, a lysosomal switch that enhances oocyte proteostasis in anticipation of fertilization may be conserved in other species.

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Acknowledgements

We thank members of the Kenyon laboratory and our colleagues at Calico for discussions and comments on the manuscript, and the Calico microscopy core, especially M. Ingaramo, for help with microscopy and sensors. We thank the E. Blackburn and P. O’Farrell laboratories for sharing equipment at UCSF. K. Sato provided the Ppie-1::gfp::lgg-1 strain. Other strains were provided by the CGC, funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). Research was performed at UCSF and then Calico, and was supported at UCSF by the George and Judy Marcus Family Foundation, the Life Extension and Chuan Lyu Foundations, and by NIH grant R37/R01 AG11816 to C.K. C.K. is now Vice President of Aging Research at Calico Life Sciences, which supported the research done at Calico. K.A.B. is an Honorary Fellow of the Jane Coffin Childs Memorial Fund.

Author information

Affiliations

  1. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California 94158, USA

    • K. Adam Bohnert
    •  & Cynthia Kenyon
  2. Calico Life Sciences, South San Francisco, California 94080, USA

    • K. Adam Bohnert
    •  & Cynthia Kenyon

Authors

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Contributions

K.A.B. and C.K. designed experiments, interpreted data, and wrote the manuscript. K.A.B. performed all experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Cynthia Kenyon.

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Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    This file contains the uncropped images of DNA gels.

  2. 2.

    Life Sciences Reporting Summary