A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase.
A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase.
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DOI：
10.1038/s41467-023-36446-8
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发表时间：
2023-02-14
影响因子：
16.6
通讯作者：
Tie, Jian-Ke
中科院分区：
文献类型：
--
作者：
Jin, Da-Yun;Chen, Xuejie;Liu, Yizhou;Williams, Craig M.;Pedersen, Lars C.;Stafford, Darrel W.;Tie, Jian-Ke
维生素K是一种重要的微量营养素，与多种人类疾病有关。Warcantine是一种维生素K拮抗剂，是最常用的口服抗凝剂。华法林过量的患者可以通过给予高剂量的维生素K来挽救，因为存在抗华法林的维生素K还原酶。尽管80多年前就发现了维生素K还原酶的功能，但其身份仍然难以捉摸。在这里，我们报告了使用全基因组CRISPR-Cas9敲除筛选和维生素K依赖性凋亡报告细胞系鉴定华法林抗性维生素K还原酶。我们发现，铁凋亡抑制蛋白1（FSP 1），泛醌氧化还原酶，是负责维生素K的减少在华法林耐药的方式，与最近的发现一致的三岛等人。FSP 1抑制剂，抑制泛醌还原，从而引发癌细胞铁凋亡，显示维生素K依赖性羧化的强烈抑制。有趣的是，二氢乳清酸脱氢酶，另一种与FSP 1功能平行的泛醌相关的铁凋亡抑制蛋白，不支持维生素K依赖性羧化。这些发现提供了新的见解，选择性地控制生理和病理过程，涉及维生素K和泛醌介导的电子转移。作者开发了一种维生素K依赖性凋亡报告细胞系，用于大规模筛选与维生素K依赖性羧化相关的酶，并鉴定了铁凋亡抑制蛋白1（FSP 1）负责抗华法林维生素K减少。
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. The authors develop a Vitamin K-dependent apoptotic reporter cell line for large-scale screening of enzymes associated with Vitamin K-dependent carboxylation and identify ferroptosis suppressor protein 1 (FSP1) as responsible for warfarin-resistant vitamin K reduction.
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影响因子：
6.7
作者：
Johnson JA;Caudle KE;Gong L;Whirl-Carrillo M;Stein CM;Scott SA;Lee MT;Gage BF;Kimmel SE;Perera MA;Anderson JL;Pirmohamed M;Klein TE;Limdi NA;Cavallari LH;Wadelius M
通讯作者：
Wadelius M
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K