A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase

Da-Yun Jin, Xuejie Chen, Yizhou Liu, Craig M. Williams, Lars C. Pedersen, Darrel W. Stafford and Jian-Ke Tie ()
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Da-Yun Jin: University of North Carolina at Chapel Hill
Xuejie Chen: University of North Carolina at Chapel Hill
Yizhou Liu: University of Queensland
Craig M. Williams: University of Queensland
Lars C. Pedersen: National Institute of Environmental Health Sciences, National Institutes of Health
Darrel W. Stafford: University of North Carolina at Chapel Hill
Jian-Ke Tie: University of North Carolina at Chapel Hill

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Vitamin K is a vital micronutrient implicated in a variety of human diseases. Warfarin, a vitamin K antagonist, is the most commonly prescribed oral anticoagulant. Patients overdosed on warfarin can be rescued by administering high doses of vitamin K because of the existence of a warfarin-resistant vitamin K reductase. Despite the functional discovery of vitamin K reductase over eight decades ago, its identity remained elusive. Here, we report the identification of warfarin-resistant vitamin K reductase using a genome-wide CRISPR-Cas9 knockout screen with a vitamin K-dependent apoptotic reporter cell line. We find that ferroptosis suppressor protein 1 (FSP1), a ubiquinone oxidoreductase, is the enzyme responsible for vitamin K reduction in a warfarin-resistant manner, consistent with a recent discovery by Mishima et al. FSP1 inhibitor that inhibited ubiquinone reduction and thus triggered cancer cell ferroptosis, displays strong inhibition of vitamin K-dependent carboxylation. Intriguingly, dihydroorotate dehydrogenase, another ubiquinone-associated ferroptosis suppressor protein parallel to the function of FSP1, does not support vitamin K-dependent carboxylation. These findings provide new insights into selectively controlling the physiological and pathological processes involving electron transfers mediated by vitamin K and ubiquinone.

Date: 2023
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DOI: 10.1038/s41467-023-36446-8

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