Chaperone AIP Couples mTORC1 Activation and Catabolic Metabolism During Neonatal Development

Korbonits, M.; Wang, X.; Barry, S.; Lim, C. T.; Suleyman, O.; De Tito, S.; Uddin, N. B.; Vignola, M. L.; Hall, C.; Perna, L.; Chapple, P.; Henson, S.; Morales, V.; Bianchi, K.; Edvardsson, V. O.; Ragnarsson, K. A.; Kristinsdottir, V. E.; Debeer, A.; Sleyp, Y.; Zinchenko, R. A.; Anderson, G.; Duchen, M.; Singh, K.; Chung, C.-Y.; Yuan, Y.; Patel, S.; Aksoy, E.; Borovikov, A.; Bjornsson, H. T.; Van Esch, H.; Czibik, G.; Tooze, S.; Brennan, C. H.; Haworth, O.

doi:10.1101/2025.09.18.677011

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bioRxiv · 10.1101/2025.09.18.677011

Chaperone AIP Couples mTORC1 Activation and Catabolic Metabolism During Neonatal Development

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Abstract

To grow and divide cells must tightly coordinate anabolic programs with the availability of nutrients and growth factors. This balance is especially critical during postnatal development, when biosynthetic and energetic demands are high, and nutrient supply and neonates have to adapt to periods of fasting. These conditions place acute stress on the proteostasis network, making autophagy essential for nutrient recycling. We found that the chaperone aryl hydrocarbon receptor-interacting protein (AIP) supports both arms of this metabolic balance: promoting anabolic PI3K-AKT signaling for mTORC1 activation and enabling catabolic processes such as proteasomal degradation and autophagy. Loss of AIP causes a severe neonatal metabolic disorder, where affected infants fail to thrive postnatally. Our findings establish AIP as a central regulator of neonatal metabolic adaptation and cellular homeostasis. One Sentence SummaryAIP integrates nutrient sensing and protein recycling to sustain neonatal survival.

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Korbonits, M., Wang, X., Barry, S., Lim, C. T., Suleyman, O., De Tito, S., Uddin, N. B., Vignola, M. L., Hall, C., Perna, L., Chapple, P., Henson, S., Morales, V., Bianchi, K., Edvardsson, V. O., Ragnarsson, K. A., Kristinsdottir, V. E., Debeer, A., Sleyp, Y., Zinchenko, R. A., Anderson, G., Duchen, M., Singh, K., Chung, C.-Y., Yuan, Y., Patel, S., Aksoy, E., Borovikov, A., Bjornsson, H. T., Van Esch, H., Czibik, G., Tooze, S., Brennan, C. H., Haworth, O.. 2025-09-18. Chaperone AIP Couples mTORC1 Activation and Catabolic Metabolism During Neonatal Development. https://doi.org/10.1101/2025.09.18.677011

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