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bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

39091747
10.1101/2024.07.25.605098
preprint
2
Article
Multi-species genome-wide CRISPR screens identify conserved suppressors of cold-induced cell death
Lam Breanna http://orcid.org/0009-0000-5502-645X

Kajderowicz Kathrin M
Keys Heather R
Roessler Julian M
Frenkel Evgeni M
Kirkland Adina
Bisht Punam
El-Brolosy Mohamed A
Jaenisch Rudolph
Bell George W
Weissman Jonathan S
Griffith Eric C
Hrvatin Sinisa http://orcid.org/0000-0001-7303-4218

06 9 2024
2024.07.25.605098https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.07.25.605098
nihpp-2024.07.25.605098.pdf
Cells must adapt to environmental changes to maintain homeostasis. One of the most striking environmental adaptations is entry into hibernation during which core body temperature can decrease from 37C to as low at 4C. How mammalian cells, which evolved to optimally function within a narrow range of temperatures, adapt to this profound decrease in temperature remains poorly understood. In this study, we conducted the first genome-scale CRISPR-Cas9 screen in cells derived from Syrian hamster, a facultative hibernator, as well as human cells to investigate the genetic basis of cold tolerance in a hibernator and a non-hibernator in an unbiased manner. Both screens independently revealed glutathione peroxidase 4 (GPX4), a selenium-containing enzyme, and associated proteins as critical for cold tolerance. We utilized genetic and pharmacological approaches to demonstrate that GPX4 is active in the cold and its catalytic activity is required for cold tolerance. Furthermore, we show that the role of GPX4 as a suppressor of cold-induced cell death extends across hibernating species, including 13-lined ground squirrels and greater horseshoe bats, highlighting the evolutionary conservation of this mechanism of cold tolerance. This study identifies GPX4 as a central modulator of mammalian cold tolerance and advances our understanding of the evolved mechanisms by which cells mitigate cold-associated damage - one of the most common challenges faced by cells and organisms in nature.
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pmc
