NYMC Faculty Publications

Non-Cell-Autonomous Regulation of Germline Proteostasis by Insulin/IGF-1 Signaling-Induced Dietary Peptide Uptake via PEPT-1

Author Type(s)

Resident/Fellow, Student, Faculty

DOI

10.1038/s44318-024-00234-x

Journal Title

EMBO Journal

First Page

4892

Last Page

4921

Document Type

Article

Publication Date

11-4-2024

Department

Medicine

Second Department

Cell Biology and Anatomy

Keywords

Germline Proteostasis, Heat Shock Factor 1, Insulin and IGF-1 Signaling, Peptide Uptake, Protein Synthesis

Disciplines

Medicine and Health Sciences

Abstract

Gametogenesis involves active protein synthesis and is proposed to rely on proteostasis. Our previous work in C. elegans indicates that germline development requires coordinated activities of insulin/IGF-1 signaling (IIS) and HSF-1, the central regulator of the heat shock response. However, the downstream mechanisms were not identified. Here, we show that depletion of HSF-1 from germ cells impairs chaperone gene expression, causing protein degradation and aggregation and, consequently, reduced fecundity and gamete quality. Conversely, reduced IIS confers germ cell resilience to HSF-1 depletion-induced protein folding defects and various proteotoxic stresses. Surprisingly, this effect was not mediated by an enhanced stress response, which underlies longevity in low IIS conditions, but by reduced ribosome biogenesis and translation rate. We found that IIS activates the expression of intestinal peptide transporter PEPT-1 by alleviating its repression by FOXO/DAF-16, allowing dietary proteins to be efficiently incorporated into an amino acid pool that fuels germline protein synthesis. Our data suggest this non-cell-autonomous pathway is critical for proteostasis regulation during gametogenesis.

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