AbstractGerminal center (GC) B cells are crucial for the generation of GCs and long-lived humoral immunity. Here we report that one-carbon metabolism determines the formation and responses of GC B cells. Upon CD40 stimulation, GC B cells selectively upregulate methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) expression to generate purines and the antioxidant glutathione.

摘要生发中心（GC）B细胞对于GC的产生和长寿体液免疫至关重要。在这里，我们报告单碳代谢决定了GC B细胞的形成和反应。在CD40刺激后，GC B细胞选择性上调亚甲基四氢叶酸脱氢酶2（MTHFD2）的表达以产生嘌呤和抗氧化剂谷胱甘肽。

MTHFD2 depletion reduces GC B cell frequency and antigen-specific antibody production. Moreover, supplementation with nucleotides and antioxidants suffices to promote GC B cell formation and function in vitro and in vivo through activation of the mammalian target of rapamycin complex 1 signaling pathway.

MTHFD2消耗降低GC B细胞频率和抗原特异性抗体产生。此外，补充核苷酸和抗氧化剂足以通过激活雷帕霉素复合物1信号通路的哺乳动物靶标在体外和体内促进GC B细胞的形成和功能。

Moreover, we found that antigen stimulation enhances YY1 binding to the Mthfd2 promoter and promotes MTHFD2 transcription. Interestingly, these findings can be generalized to the pentose phosphate pathway, which is another major source of reducing power and nucleotides. Therefore, these results suggest that an increased capacity for nucleotide synthesis and redox balance is required for GC B cell formation and responses, revealing a key aspect of GC B cell fate determination..

此外，我们发现抗原刺激增强YY1与Mthfd2启动子的结合并促进Mthfd2转录。有趣的是，这些发现可以推广到戊糖磷酸途径，这是还原力和核苷酸的另一个主要来源。因此，这些结果表明，GC B细胞的形成和反应需要增加核苷酸合成和氧化还原平衡的能力，这揭示了GC B细胞命运决定的关键方面。。

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Fig. 1: Increased one-carbon metabolism is a metabolic feature of GC B cells.Fig. 2: Loss of MTHFD2 impairs GC B cell formation and GC responses.Fig. 3: The availability of nucleotides and oxidants suffices for GC B cell formation and functions.Fig. 4: The mTORC1 signaling pathway links nucleoside and antioxidant sufficiency to GC B cell formation.Fig.

图1：增加的单碳代谢是GC B细胞的代谢特征。图2:MTHFD2的丢失会损害GC B细胞的形成和GC反应。图3：核苷酸和氧化剂的可用性足以满足GC B细胞的形成和功能。图4:mTORC1信号通路将核苷和抗氧化剂充足性与GC B细胞形成联系起来。图。

5: MTHFD2 is a transcriptional target of YY1 that contributes to GC B cell formation by upregulating purine biosynthesis and antioxidant capacity.Fig. 6: The upregulation of antioxidant capacity and purine availability is a common mechanism for GC B cell formation and responses..

5： MTHFD2是YY1的转录靶标，通过上调嘌呤生物合成和抗氧化能力来促进GC B细胞的形成。。。

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ReferencesVictora, G. D. & Nussenzweig, M. C. Germinal centers. Annu Rev. Immunol. 30, 429–457 (2012).Article

参考文献Victora，G.D。和Nussenzweig，M.C。生发中心。年度免疫修订版。30429-457（2012）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Klein, U. & Dalla-Favera, R. Germinal centres: role in B-cell physiology and malignancy. Nat. Rev. Immunol. 8, 22–33 (2008).Article

Klein，U。＆Dalla-Favera，R。生发中心：在B细胞生理学和恶性肿瘤中的作用。国家免疫修订版。。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Victora, G. D. et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143, 592–605 (2010).Article

Victora，G.D.等人。通过多光子显微镜和可光激活荧光报告基因揭示生发中心动力学。细胞143592-605（2010）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Jellusova, J. Metabolic control of B cell immune responses. Curr. Opin. Immunol. 63, 21–28 (2020).Article

Jellusova，J。B细胞免疫应答的代谢控制。货币。奥平。免疫。63,21-28（2020）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Caro-Maldonado, A. et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J. Immunol. 192, 3626–3636 (2014).Article

Caro-Maldonado，A。等人。代谢重编程是抗体产生所必需的，抗体产生在无反应性中被抑制，但在慢性BAFF暴露的B细胞中被夸大。J、 免疫。1923626-3636（2014）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Jayachandran, N. et al. TAPP adaptors control B cell metabolism by modulating the phosphatidylinositol 3-kinase signaling pathway: a novel regulatory circuit preventing autoimmunity. J. Immunol. 201, 406–416 (2018).Article

Jayachandran，N。等人。TAPP衔接子通过调节磷脂酰肌醇3-激酶信号通路来控制B细胞代谢：一种预防自身免疫的新型调节电路。J、 免疫。201406-416（2018）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Diaz-Munoz, M. D. et al. The RNA-binding protein HuR is essential for the B cell antibody response. Nat. Immunol. 16, 415–425 (2015).Article

Diaz-Munoz，M.D.等人。RNA结合蛋白HuR对于B细胞抗体反应至关重要。。16415-425（2015）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Dufort, F. J. et al. Glucose-dependent de novo lipogenesis in B lymphocytes: a requirement for ATP–citrate lyase in lipopolysaccharide-induced differentiation. J. Biol. Chem. 289, 7011–7024 (2014).Article

Dufort，F.J.等人，《B淋巴细胞中葡萄糖依赖性新生脂肪生成：脂多糖诱导分化中ATP-柠檬酸裂解酶的需求》。J、 生物。化学。2897011–7024（2014）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Cheng, J. et al. Fumarate suppresses B-cell activation and function through direct inactivation of LYN. Nat. Chem. Biol. 18, 954–962 (2022).Article

Cheng，J。等人。富马酸盐通过直接灭活LYN来抑制B细胞活化和功能。自然化学。生物学18954-962（2022）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Cho, S. H. et al. Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature 537, 234–238 (2016).Article

Cho，S.H.等人。生发中心缺氧和缺氧反应系统对抗体质量的调节。自然537234-238（2016）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Semenza, G. L., Roth, P. H., Fang, H. M. & Wang, G. L. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J. Biol. Chem. 269, 23757–23763 (1994).Article

Semenza，G.L.，Roth，P.H.，Fang，H.M。＆Wang，G.L。缺氧诱导因子1对编码糖酵解酶的基因的转录调控。J、 生物。化学。26923757-23763（1994）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Jellusova, J. et al. GSK3 is a metabolic checkpoint regulator in B cells. Nat. Immunol. 18, 303–312 (2017).Article

Jellusova，J。等人。GSK3是B细胞中的代谢检查点调节剂。。18303-312（2017）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Sharma, R. et al. Distinct metabolic requirements regulate B cell activation and germinal center responses. Nat. Immunol. 24, 1358–1369 (2023).Article

Sharma，R。等人。不同的代谢需求调节B细胞活化和生发中心反应。。241358-1369（2023）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Weisel, F. J. et al. Germinal center B cells selectively oxidize fatty acids for energy while conducting minimal glycolysis. Nat. Immunol. 21, 331–342 (2020).Article

Weisel，F.J。等人生发中心B细胞选择性地氧化脂肪酸以获得能量，同时进行最小的糖酵解。。21331-342（2020）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Chen, D. et al. Coupled analysis of transcriptome and BCR mutations reveals role of OXPHOS in affinity maturation. Nat. Immunol. 22, 904–913 (2021).Article

Chen，D。等人。转录组和BCR突变的耦合分析揭示了OXPHOS在亲和力成熟中的作用。。22904-913（2021）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Ducker, G. S. et al. Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway. Cell Metab. 23, 1140–1153 (2016).Article

Ducker，G.S.等人。胞质单碳通量的逆转补偿了线粒体叶酸途径的丧失。细胞代谢。231140-1153（2016）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Galibert, L. et al. CD40 and B cell antigen receptor dual triggering of resting B lymphocytes turns on a partial germinal center phenotype. J. Exp. Med. 183, 77–85 (1996).Article

Galibert，L。等人。CD40和B细胞抗原受体双重触发静息B淋巴细胞开启部分生发中心表型。J、 实验医学183，77-85（1996）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

D’Avola, A. et al. PHGDH is required for germinal center formation and is a therapeutic target in MYC-driven lymphoma. J. Clin. Invest. 132, e153436 (2022).Article

D'Avola，A。等人。PHGDH是生发中心形成所必需的，并且是MYC驱动的淋巴瘤的治疗靶标。J、 临床。投资。132，e153436（2022）。文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Haniuda, K., Nojima, T. & Kitamura, D. In vitro-induced germinal center B cell culture system. Methods Mol. Biol. 1623, 125–133 (2017).Article

。方法分子生物学。1623125-133（2017）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Kawai, J. et al. Structure-based design and synthesis of an isozyme-selective MTHFD2 inhibitor with a tricyclic coumarin scaffold. ACS Med. Chem. Lett. 10, 893–898 (2019).Article

。ACS医学化学。利特。10893-898（2019）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Li, G., Wu, J., Li, L. & Jiang, P. p53 deficiency induces MTHFD2 transcription to promote cell proliferation and restrain DNA damage. Proc. Natl Acad. Sci. USA 118, e2019822118 (2021).Article

Li，G.，Wu，J.，Li，L。＆Jiang，P。p53缺陷诱导MTHFD2转录以促进细胞增殖并抑制DNA损伤。程序。国家科学院。科学。美国118，e2019822118（2021）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Gustafsson Sheppard, N. et al. The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation. Sci. Rep. 5, 15029 (2015).Article

叶酸偶联酶MTHFD2是一种核蛋白，可促进细胞增殖。科学。代表515029（2015）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Nojima, T. et al. In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo. Nat. Commun. 2, 465 (2011).Article

Nojima，T。等人。体外衍生的生发中心B细胞在体内差异产生记忆B或浆细胞。国家公社。2465（2011）。文章

PubMed

PubMed

Google Scholar

谷歌学者

Zhao, R. et al. A GPR174–CCL21 module imparts sexual dimorphism to humoral immunity. Nature 577, 416–420 (2020).Article

Zhao，R。等人。GPR174-CCL21模块赋予体液免疫性别二态性。自然577416-420（2020）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Emmanuel, N. et al. Purine nucleotide availability regulates mTORC1 activity through the Rheb GTPase. Cell Rep. 19, 2665–2680 (2017).Article

Emmanuel，N。等人。嘌呤核苷酸的可用性通过Rheb GTPase调节mTORC1活性。Cell Rep.192665–2680（2017）。文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Jiang, P., Du, W. & Wu, M. Regulation of the pentose phosphate pathway in cancer. Protein Cell 5, 592–602 (2014).Article

Jiang，P.，Du，W。＆Wu，M。癌症中戊糖磷酸途径的调节。蛋白质细胞5592-602（2014）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Patra, K. C. & Hay, N. The pentose phosphate pathway and cancer. Trends Biochem. Sci. 39, 347–354 (2014).Article

Patra，K.C。和Hay，N。戊糖磷酸途径和癌症。趋势生物化学。科学。39347-354（2014）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Franchina, D. G. et al. Glutathione-dependent redox balance characterizes the distinct metabolic properties of follicular and marginal zone B cells. Nat. Commun. 13, 1789 (2022).Article

Franchina，D.G.等人。谷胱甘肽依赖性氧化还原平衡表征了滤泡和边缘区B细胞的独特代谢特性。国家公社。131789（2022）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wang, L. W. et al. Epstein–Barr-virus-induced one-carbon metabolism drives B cell transformation. Cell Metab. 30, 539–555 (2019).Article

Wang，L.W.等人。爱泼斯坦-巴尔病毒诱导的单碳代谢驱动B细胞转化。细胞代谢。30539-555（2019）。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Download referencesAcknowledgementsWe thank H. Qi, M. Xu, W. Liu, L. Yu and D. Pan at Tsinghua University for materials and/or technical assistance. We thank all members of the Jiang laboratory for their technical assistance and/or discussions. We thank X. Liu, L. Xu, X. Wang and W. Wang for their help with the LC–MS/MS experiments.

下载参考文献致谢我们感谢清华大学的H.Qi，M.Xu，W.Liu，L.Yu和D.Pan提供的材料和/或技术援助。我们感谢江实验室所有成员的技术援助和/或讨论。我们感谢X.Liu，L.Xu，X.Wang和W.Wang在LC-MS/MS实验中的帮助。

This work was supported by the National Natural Science Foundation of China (82125030 and 82341022 to P.J.) and the National Natural Science Foundation of China (82273227 to J.W.). J.W. was also supported by the Shuimu Tsinghua Scholar Program.Author informationAuthor notesThese authors contributed equally: Jun Wu, Jiawen Zhou, Gen Li.Authors and AffiliationsState Key Laboratory of Molecular Oncology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, ChinaJun Wu, Jiawen Zhou, Gen Li, Xuan Sun, Haiyan Chen & Peng JiangSchool of Pharmaceutical Sciences, Xiamen University, Xiamen, ChinaJun WuDepartment of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, ChinaChen XiangAuthorsJun WuView author publicationsYou can also search for this author in.

这项工作得到了国家自然科学基金（P.J.的82125030和82341022）和国家自然科学基金（J.W.的82273227）的支持。J、 W.也得到了水木清华学者计划的支持。作者信息作者注意到这些作者做出了同样的贡献：吴军，周家文，李根。作者和附属机构清华大学生命科学学院清华北京生命科学中心分子肿瘤学国家重点实验室，北京，中国吴军，周家文，李根，孙萱，陈海燕和彭江厦门大学药物科学学院，厦门，中国吴军清华大学医学院基础医学系，北京，中国陈翔作者吴军观点作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsJ.W., G.L. and P.J. designed the experiments. J.W. and J.Z. performed all of the experiments except those mentioned below. G.L. performed some of the animal and imaging experiments. X.S., X.C. and H.C. provided technical assistance. J.W. collected, analyzed and organized the data with help from J.Z.

PubMed谷歌学术贡献。W、 ，G.L.和P.J.设计了实验。J、 W.和J.Z.进行了所有实验，除了下面提到的实验。G、 L.进行了一些动物和成像实验。十、 美国、X.C.和H.C.提供了技术援助。J、 W.在J.Z.的帮助下收集，分析和组织数据。

P.J. supervised the research and interpreted the data. P.J. wrote the paper with the help of W.J. and J.Z. All authors commented on the paper.Corresponding authorCorrespondence to.

P、 J.监督研究并解释数据。P、 J.在W.J.和J.Z.的帮助下撰写了这篇论文。所有作者都对这篇论文发表了评论。对应作者对应。

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Nature Chemical Biology thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended dataExtended Data Fig. 1 GC B cells display increased one-carbon metabolism activity.a, Schematic illustration of carbon transition from serine into purines through one-carbon metabolism catalyzed by SHMT2 and MTHFD2.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据扩展数据图1 GC B细胞显示增加的单碳代谢活性。a，通过SHMT2和MTHFD2催化的单碳代谢从丝氨酸向嘌呤的碳转变的示意图。

Red circle represents 13C from serine. b, Mass isotopomer distribution (MID) of AMP, GMP, CMP and UMP in B cells cultured in medium containing 13C3-serine after 24 or 48 hours of activation with anti-CD40+IgM+IgG F(ab)2. Cells per group from n = 3 mice. c-f, Germinal center B cells, follicular B cells, marginal zone B cells and transitional B cells were isolated from splenocytes of 7-day NP-KLH-immunized C57BL/6 mice, and splenocytes or splenocytes pre-treated for 24 h with GSH or NAC were analyzed for glutathione levels by LC-MS (c), or ROS levels by DCF staining (d) and survival by PI staining (e) followed by FACS analysis.

红色圆圈代表来自丝氨酸的13C。b、 用抗CD40+IgM+IgG F（ab）2激活24或48小时后，在含有13C3丝氨酸的培养基中培养的b细胞中AMP，GMP，CMP和UMP的质量同位素分布（MID）。来自n=3只小鼠的每组细胞。从7天NP-KLH免疫的C57BL/6小鼠的脾细胞中分离c-f，生发中心B细胞，滤泡B细胞，边缘区B细胞和过渡性B细胞，并用GSH或NAC预处理24小时的脾细胞或脾细胞通过LC-MS（c）分析谷胱甘肽水平，或通过DCF染色（d）分析ROS水平，并通过PI染色（e）分析存活率，然后进行FACS分析。

FACS plots are shown (f). n = 3 mice per group. All data are the mean ± SEM.; Two-tailed Student’s t-test (c-e); ns, not significant.Source dataExtended Data Fig. 2 Serine supports T cell-dependent GC B cell differentiation.a,b, Levels of 13C-labled glycine (a), or methionine, CMP, TMP and UMP (b) in naive B cells activated by anti-CD40+IgG+IgM F(ab)2 in medium containing 400 µM 13C3-serine for the indicated time points.

。每组n=3只小鼠。所有数据均为平均值±SEM。；双尾学生t检验（c-e）；ns，不显着。来源数据扩展数据图2丝氨酸支持T细胞依赖性GC B细胞分化。在指定的时间点，在含有400μM13C3丝氨酸的培养基中，抗CD40+IgG+IgM F（ab）2激活的幼稚B细胞中，a，B，13C标记的甘氨酸（a）或蛋氨酸，CMP，TMP和UMP（B）的水平。

Cells per group from n = 3 mice c, d, Mouse naïve B cells activated by anti-CD40 + mIL4 for 72 hours in medium with (+) or without (-) serine and glycine (Serine/Glycine, SG) were stained with CFSE (c) or Ki67 antibody (d) and analyzed by FACS. Cells per group from n = 3 mice. e, f, Male C57BL/6 mice (6 weeks old) fed on serine/glycine-free diet were intr.

在含有（+）或不含（-）丝氨酸和甘氨酸（丝氨酸/甘氨酸，SG）的培养基中，由抗CD40+ mIL4激活72小时的来自n=3只小鼠c，d，小鼠幼稚B细胞的每组细胞用CFSE（c）或Ki67抗体（d）染色并通过FACS分析。来自n=3只小鼠的每组细胞。e、 f，喂食无丝氨酸/甘氨酸饮食的雄性C57BL/6小鼠（6周龄）是intr。

Nat Chem Biol (2024). https://doi.org/10.1038/s41589-024-01690-6Download citationReceived: 24 July 2023Accepted: 03 July 2024Published: 26 July 2024DOI: https://doi.org/10.1038/s41589-024-01690-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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