Redox activation of ATG5 licenses autophagy upon nutrient restriction
- 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA; Howard Hughes
Abstract
Dietary restriction (DR) protects against metabolic disease, extends lifespan, and is associated with remodeling of tissue reactive oxygen species (ROS). ROS control biological adaptation through reversible oxidation of protein cysteines, yet the targets of DR-initiated redox signaling are unknown. Here we generate OxiDR, a tissue-resolved atlas of the cysteine redox proteome that quantifies oxidation state under DR. Rather than oxidizing the proteome broadly, DR selectively targets a high-amplitude set of cysteines in a tissue-specific manner, allowing systematic classification of biological processes subject to DR-mediated redox regulation. Among the cysteines most highly oxidized upon DR is Cys19 of the core autophagy protein ATG5. We show oxidation of Cys19 is required for ATG5-mediated autophagosome formation and for autophagy triggered by nutrient restriction in human cells and mice. Reversible oxidation of this cysteine promotes ATG5 binding to ATG10, thus forming the ATG5-ATG12 conjugate that lipidates LC3B/ATG8 and matures the autophagosome. In mice, loss of this redox switch prevents effective initiation of autophagy upon nutrient restriction, resulting in gross tissue pathology and rapid onset of mortality. The autophagic response to nutrient restriction is thus gated by oxidation of a single cysteine.
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BibTeX
@misc{shin2026redox,
title = {{Redox activation of ATG5 licenses autophagy upon nutrient restriction}},
author = {S. Shin and E. D. Korobkina and C. Lennicke and N. Burger and B. Zhang and H. Xiao and Y. Wang and J. J. Petrocelli and S. M. Wei and D. Wood and Y. Lei and X. Zhang and M. C. Perez-Matos and M. A. Sharif and J. Zhang and H. M. Cocheme and W. B. Mair and E. T. Chouchani},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.23.753803},
url = {https://www.biorxiv.org/content/10.64898/2026.09.23.753803v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Redox activation of ATG5 licenses autophagy upon nutrient restriction
AU - S. Shin
AU - E. D. Korobkina
AU - C. Lennicke
AU - N. Burger
AU - B. Zhang
AU - H. Xiao
AU - Y. Wang
AU - J. J. Petrocelli
AU - S. M. Wei
AU - D. Wood
AU - Y. Lei
AU - X. Zhang
AU - M. C. Perez-Matos
AU - M. A. Sharif
AU - J. Zhang
AU - H. M. Cocheme
AU - W. B. Mair
AU - E. T. Chouchani
PY - 2026
DA - 2026/09/23
PB - bioRxiv
DO - 10.64898/2026.09.23.753803
UR - https://www.biorxiv.org/content/10.64898/2026.09.23.753803v1
AB - Dietary restriction (DR) protects against metabolic disease, extends lifespan, and is associated with remodeling of tissue reactive oxygen species (ROS). ROS control biological adaptation through reversible oxidation of protein cysteines, yet the targets of DR-initiated redox signaling are unknown. Here we generate OxiDR, a tissue-resolved atlas of the cysteine redox proteome that quantifies oxidation state under DR. Rather than oxidizing the proteome broadly, DR selectively targets a high-amplitude set of cysteines in a tissue-specific manner, allowing systematic classification of biological processes subject to DR-mediated redox regulation. Among the cysteines most highly oxidized upon DR is Cys19 of the core autophagy protein ATG5. We show oxidation of Cys19 is required for ATG5-mediated autophagosome formation and for autophagy triggered by nutrient restriction in human cells and mice. Reversible oxidation of this cysteine promotes ATG5 binding to ATG10, thus forming the ATG5-ATG12 conjugate that lipidates LC3B/ATG8 and matures the autophagosome. In mice, loss of this redox switch prevents effective initiation of autophagy upon nutrient restriction, resulting in gross tissue pathology and rapid onset of mortality. The autophagic response to nutrient restriction is thus gated by oxidation of a single cysteine.
ER -