A PTEN variant uncouples longevity from impaired fitness in Caenorhabditis elegans with reduced insulin/IGF-1 signaling

Hae-Eun H. Park, Wooseon Hwang, Seokjin Ham, Eunah Kim, Ozlem Altintas, Sangsoon Park, Heehwa G. Son, Yujin Lee, Dongyeop Lee, Won Do Heo and Seung-Jae V. Lee ()
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Hae-Eun H. Park: Korea Advanced Institute of Science and Technology
Wooseon Hwang: Pohang University of Science and Technology
Seokjin Ham: Korea Advanced Institute of Science and Technology
Eunah Kim: Korea Advanced Institute of Science and Technology
Ozlem Altintas: Pohang University of Science and Technology
Sangsoon Park: Korea Advanced Institute of Science and Technology
Heehwa G. Son: Korea Advanced Institute of Science and Technology
Yujin Lee: Korea Advanced Institute of Science and Technology
Dongyeop Lee: Pohang University of Science and Technology
Won Do Heo: Korea Advanced Institute of Science and Technology
Seung-Jae V. Lee: Korea Advanced Institute of Science and Technology

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Insulin/IGF-1 signaling (IIS) regulates various physiological aspects in numerous species. In Caenorhabditis elegans, mutations in the daf-2/insulin/IGF-1 receptor dramatically increase lifespan and immunity, but generally impair motility, growth, and reproduction. Whether these pleiotropic effects can be dissociated at a specific step in insulin/IGF-1 signaling pathway remains unknown. Through performing a mutagenesis screen, we identified a missense mutation daf-18(yh1) that alters a cysteine to tyrosine in DAF-18/PTEN phosphatase, which maintained the long lifespan and enhanced immunity, while improving the reduced motility in adult daf-2 mutants. We showed that the daf-18(yh1) mutation decreased the lipid phosphatase activity of DAF-18/PTEN, while retaining a partial protein tyrosine phosphatase activity. We found that daf-18(yh1) maintained the partial activity of DAF-16/FOXO but restricted the detrimental upregulation of SKN-1/NRF2, contributing to beneficial physiological traits in daf-2 mutants. Our work provides important insights into how one evolutionarily conserved component, PTEN, can coordinate animal health and longevity.

Date: 2021
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DOI: 10.1038/s41467-021-25920-w

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