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Metabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction

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  • Charlotte M. François

    (Université Côte d’Azur, CNRS, Inserm, Institut de Biologie Valrose)

  • Thomas Pihl

    (Université Côte d’Azur, CNRS, Inserm, Institut de Biologie Valrose)

  • Marion Dunoyer de Segonzac

    (Université Côte d’Azur, CNRS, Inserm, Institut de Biologie Valrose)

  • Chloé Hérault

    (Université Côte d’Azur, CNRS, Inserm, Institut de Biologie Valrose)

  • Bruno Hudry

    (Université Côte d’Azur, CNRS, Inserm, Institut de Biologie Valrose)

Abstract

The molecular mechanisms connecting cellular metabolism with differentiation remain poorly understood. Here, we find that metabolic signals contribute to stem cell differentiation and germline homeostasis during Drosophila melanogaster spermatogenesis. We discovered that external citrate, originating outside the gonad, fuels the production of Acetyl-coenzyme A by germline ATP-citrate lyase (dACLY). We show that this pathway is essential during the final spermatogenic stages, where a high Acetyl-coenzyme A level promotes NatB-dependent N-terminal protein acetylation. Using genetic and biochemical experiments, we establish that N-terminal acetylation shields key target proteins, essential for spermatid differentiation, from proteasomal degradation by the ubiquitin ligase dUBR1. Our work uncovers crosstalk between metabolism and proteome stability that is mediated via protein post-translational modification. We propose that this system coordinates the metabolic state of the organism with gamete production. More broadly, modulation of proteome turnover by circulating metabolites may be a conserved regulatory mechanism to control cell functions.

Suggested Citation

  • Charlotte M. François & Thomas Pihl & Marion Dunoyer de Segonzac & Chloé Hérault & Bruno Hudry, 2023. "Metabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42496-9
    DOI: 10.1038/s41467-023-42496-9
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    1. Nina McTiernan & Ine Kjosås & Thomas Arnesen, 2025. "Illuminating the impact of N-terminal acetylation: from protein to physiology," Nature Communications, Nature, vol. 16(1), pages 1-15, December.

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