Non-cell-autonomous regulation of germline proteostasis by insulin/IGF-1 signaling via the intestinal peptide transporter PEPT-1

Muhammad, T.; Edwards, S. L.; Morphis, A. C.; Johnson, M. V.; Oliveira, V. D.; Chamera, T.; Liu, S.; Nguyen, N. G. T.; Li, J.

doi:10.1101/2024.02.22.581543

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bioRxiv · 10.1101/2024.02.22.581543

Non-cell-autonomous regulation of germline proteostasis by insulin/IGF-1 signaling via the intestinal peptide transporter PEPT-1

Muhammad, T.·Edwards, S. L.·Morphis, A. C.·Johnson, M. V.·Oliveira, V. D.·Chamera, T.·Liu, S.·Nguyen, N. G. T.·Li, J.

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Abstract

Gametogenesis involves active protein synthesis and heavily relies on proteostasis. How animals regulate germline proteostasis at the organismal level is poorly understood. Taking C. elegans as a model, we show that germline proteostasis requires coupled activities of HSF-1-dependent protein folding and insulin/IGF-1 signaling controlled protein synthesis. Depletion of HSF-1 from germ cells impairs chaperone gene expression, causing protein degradation and aggregation and, consequently, declines in fecundity and gamete quality. Reduced insulin/IGF-1 signaling confers germ cells resilience to limited protein folding capacity and proteotoxic stress by lowering ribosome biogenesis and the rate of translation. Interestingly, insulin/IGF-1 signaling promotes the expression of the evolutionarily conserved intestinal peptide transporter PEPT-1 via its downstream transcription factor FOXO/DAF-16, therefore allowing dietary proteins to be incorporated into an amino acid pool that fuels protein synthesis in the germline. We propose that this non-cell-autonomous pathway plays a critical role in regulating proteostasis in gametogenesis. TeaserInsulin/IGF-1 signaling regulates proteostasis in gametogenesis via the control of dietary protein absorption.

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Muhammad, T., Edwards, S. L., Morphis, A. C., Johnson, M. V., Oliveira, V. D., Chamera, T., Liu, S., Nguyen, N. G. T., Li, J.. 2024-02-25. Non-cell-autonomous regulation of germline proteostasis by insulin/IGF-1 signaling via the intestinal peptide transporter PEPT-1. https://doi.org/10.1101/2024.02.22.581543

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