4.8 Article

RIPK1 regulates starvation resistance by modulating aspartate catabolism

Journal

NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-021-26423-4

Keywords

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Funding

  1. National Natural Science Foundation of China [31801167, 31971356, 92057114]
  2. Shanghai Municipal Science and TechnologyMajor Project [2019SHZDZX02]
  3. Shanghai Municipal Science and Technology Commission [17YF1424200]
  4. Excellent Young Scholar Fund from the National Natural Science Foundation of China [22022411]

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RIPK1 serves as a critical metabolic regulator that affects neonatal survival under severe starvation conditions, by modulating aspartate levels and autophagy.
RIPK1 is critical for normal development and cell death. Here, the authors identify a metabolic role for RIPK1 in aspartate homeostasis, as increased aspartate levels in RIPK1-deficient cells inhibits starvation-induced autophagy by ULK1. RIPK1 is a crucial regulator of cell death and survival. Ripk1 deficiency promotes mouse survival in the prenatal period while inhibits survival in the early postnatal period without a clear mechanism. Metabolism regulation and autophagy are critical to neonatal survival from severe starvation at birth. However, the mechanism by which RIPK1 regulates starvation resistance and survival remains unclear. Here, we address this question by discovering the metabolic regulatory role of RIPK1. First, metabolomics analysis reveals that Ripk1 deficiency specifically increases aspartate levels in both mouse neonates and mammalian cells under starvation conditions. Increased aspartate in Ripk1(-/-) cells enhances the TCA flux and ATP production. The energy imbalance causes defective autophagy induction by inhibiting the AMPK/ULK1 pathway. Transcriptional analyses demonstrate that Ripk1(-/-) deficiency downregulates gene expression in aspartate catabolism by inactivating SP1. To summarize, this study reveals that RIPK1 serves as a metabolic regulator responsible for starvation resistance.

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