水稻miRNAs响应生物胁迫研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2025-0061

摘要/Abstract

摘要：

水稻生产过程中常常面临着各种真菌、细菌、病毒以及害虫等生物胁迫，严重威胁水稻生长与产量，提高水稻自身抗性是防控病虫危害最经济有效的方式。miRNAs是一类长约20-24个核苷酸的内源性非编码小RNA，通过降解靶mRNAs或抑制mRNAs翻译来负调控基因的表达。近些年，水稻miRNAs在响应生物胁迫的功能研究中取得了诸多进展，水稻miRNAs通过调控多种转录因子、转运蛋白、内源信号分子、信号受体、氧化酶、水解酶以及激酶等参与模式触发免疫（PTI）和效应子触发免疫（ETI）信号途径，直接或间接调控水稻对生物胁迫的耐受性。部分miRNAs在兼顾水稻产量和抗性上发挥了关键作用，如miR156、miR168、miR396、miR162a、miR1873、miR1871以及miR1432等，为培育高产抗病水稻品种提供了重要思路。然而，水稻miRNAs响应生物胁迫的研究大多数集中在下游靶基因的鉴定和表征，应加大对上游调控元件的研究，同时全面地剖析miRNAs介导的生物胁迫信号的传递并细化各组件的功能及它们之间的互动关系，从而为提高操纵miRNA表达的效率以改良水稻品种奠定基础。本文综述水稻miRNAs响应稻瘟病、白叶枯病、条纹叶枯病、病毒病以及褐飞虱等生物胁迫的功能与机制，并提出未来需要关注和进一步研究的科学问题，以期为水稻分子育种提供策略。

关键词: 水稻, miRNAs, 生物胁迫, 靶基因, 作用机制

Abstract:

During the rice production process, rice (Oryza sativa) often faces various biotic stresses such as fungi, bacteria, viruses, and pests, which seriously threaten rice growth and yield. Improving the inherent resistance of rice is the most economical and effective way to resist pests and pathogens. MiRNAs are a class of endogenous non-coding small RNAs approximately 20-24 nucleotides in length,which negatively regulate gene expression by degrading target mRNAs or inhibiting translation. In recent years, significant progress has been achieved in the functional research of rice miRNAs in response to biotic stresses. Rice miRNAs participate in the pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) signaling pathways through a variety of transcription factors, transporters, endogenous signaling molecules, signal receptors, oxidases, hydrolases, and kinases, etc., directly or indirectly regulating the tolerance of rice to biotic stresses. Several miRNAs, such as miR156, miR168, miR396, miR162a, miR1873, miR1871, and miR1432, play critical roles in balancing rice yield and resistance, offering important insights for breeding high-yielding and disease-resistant varieties. However, most current studies on rice miRNAs in responses to biotic stress focus on identifying and characterizing downstream target genes. Future efforts should intensify research on upstream regulatory elements and comprehensively dissect the signal transduction pathways mediated by miRNAs, specifically clarifying the functions of individual components and their interactive networks. This will lay a foundation for improving the efficiency of miRNA expression manipulation in rice varietal improvement. This paper mainly reviews the functions of rice miRNAs in response to biotic stresses such as rice blast, bacterial blight, stripe disease, viral diseases, and brown planthoppers. It also proposes scientific questions that need attention and further research in the future, aiming to provide strategies for rice molecular breeding.

Key words: rice, miRNAs, biotic stress, target genes, action mechanism

侯鹰翔, 费思恬, 黎妮, 李兰, 宋松泉, 王伟平, 张超. 水稻miRNAs响应生物胁迫研究进展[J]. 生物技术通报, 2025, 41(7): 69-80.

HOU Ying-xiang, FEI Si-tian, LI Ni, LI Lan, SONG Song-quan, WANG Wei-ping, ZHANG Chao. Research Progress in Response of Rice miRNAs to Biotic Stress[J]. Biotechnology Bulletin, 2025, 41(7): 69-80.

图/表 2

图1 水稻miRNAs调控稻瘟病抗性机制示意图

Fig. 1 Schematic diagram of the regulatory mechanism of rice miRNAs in rice blast resistance

图2 水稻miRNAs调控其他病虫害抗性机制示意图A：水稻miRNAs调控白叶枯抗性；B：水稻miRNAs调控纹枯病抗性；C：水稻miRNAs调控褐飞虱抗性；D：水稻miRNAs调控病毒病抗性

Fig. 2 Schematic diagrams of regulatory mechanisms of rice miRNAs in resistance to various pests and diseasesA: Rice miRNAs regulate bacterial blight resistance. B: Rice miRNAs regulate sheath blight resistance. C: Rice miRNAs regulate brown planthopper resistance. D: Rice miRNAs regulate rice virus disease resistance

参考文献 90

[16]	Campo S, Peris-Peris C, Siré C, et al. Identification of a novel microRNA (miRNA) from rice that targets an alternatively spliced transcript of the Nramp6 (Natural resistance-associated macrophage protein 6) gene involved in pathogen resistance [J]. New Phytol, 2013, 199(1): 212-227.
[17]	Peris-Peris C, Serra-Cardona A, Sánchez-Sanuy F, et al. Two NRAMP6 isoforms function as iron and manganese transporters and contribute to disease resistance in rice [J]. Mol Plant Microbe Interact, 2017, 30(5): 385-398.
[18]	Sánchez-Sanuy F, Peris-Peris C, Tomiyama S, et al. Osa-miR7695 enhances transcriptional priming in defense responses against the rice blast fungus [J]. BMC Plant Biol, 2019, 19(1): 563.
[19]	Li Y, Lu YG, Shi Y, et al. Multiple rice microRNAs are involved in immunity against the blast fungus Magnaporthe oryzae [J]. Plant Physiol, 2014, 164(2): 1077-1092.
[20]	Li Y, Cao XL, Zhu Y, et al. Osa-miR398b boosts H₂O₂ production and rice blast disease-resistance via multiple superoxide dismutases [J]. New Phytol, 2019, 222(3): 1507-1522.
[21]	Feng Q, Wang H, Yang XM, et al. Osa-miR160a confers broad-spectrum resistance to fungal and bacterial pathogens in rice [J]. New Phytol, 2022, 236(6): 2216-2232.
[22]	Sheng C, Yu DL, Li X, et al. OsAPX1 positively contributes to rice blast resistance [J]. Front Plant Sci, 2022, 13: 843271.
[23]	Wang H, Wang ZX, Tian HY, et al. The miR172a-SNB module orchestrates both induced and adult-plant resistance to multiple diseases via MYB30-mediated lignin accumulation in rice [J]. Mol Plant, 2025, 18(1): 59-75.
[24]	Ichimaru K, Yamaguchi K, Harada K, et al. Cooperative regulation of PBI1 and MAPKs controls WRKY45 transcription factor in rice immunity [J]. Nat Commun, 2022, 13(1): 2397.
[25]	Cheng XL, He Q, Tang S, et al. The miR172/IDS1 signaling module confers salt tolerance through maintaining ROS homeostasis in cereal crops [J]. New Phytol, 2021, 230(3): 1017-1033.
[26]	Li WT, Wang K, Chern M, et al. Sclerenchyma cell thickening through enhanced lignification induced by OsMYB30 prevents fungal penetration of rice leaves [J]. New Phytol, 2020, 226(6): 1850-1863.
[27]	Li XP, Ma XC, Wang H, et al. Osa-miR162a fine-tunes rice resistance to Magnaporthe oryzae and Yield [J]. Rice, 2020, 13(1): 38.
[28]	Zhang DD, Liu MX, Tang MZ, et al. Repression of microRNA biogenesis by silencing of OsDCL1 activates the basal resistance to Magnaporthe oryzae in rice [J]. Plant Sci, 2015, 237: 24-32.
[29]	Barik S, SarkarDas S, Singh A, et al. Phylogenetic analysis reveals conservation and diversification of micro RNA166 genes among diverse plant species [J]. Genomics, 2014, 103(1): 114-121.
[30]	Baldrich P, Hsing YC, San Segundo B. Genome-wide analysis of polycistronic microRNAs in cultivated and wild rice [J]. Genome Biol Evol, 2016, 8(4): 1104-1114.
[31]	Salvador-Guirao R, Hsing YI, San Segundo B. The polycistronic miR166k-166h positively regulates rice immunity via post-transcriptional control of EIN2 [J]. Front Plant Sci, 2018, 9: 337.
[32]	Yang C, Li W, Cao JD, et al. Activation of ethylene signaling pathways enhances disease resistance by regulating ROS and phytoalexin production in rice [J]. Plant J, 2017, 89(2): 338-353.
[33]	Qiu JH, Liu ZQ, Xie JH, et al. Dual impact of ambient humidity on the virulence of Magnaporthe oryzae and basal resistance in rice [J]. Plant Cell Environ, 2022, 45(12): 3399-3411.
[34]	Chen JF, Zhao ZX, Li Y, et al. Fine-tuning roles of Osa-miR159a in rice immunity against Magnaporthe oryzae and development [J]. Rice, 2021, 14(1): 26.
[35]	Campo S, Sánchez-Sanuy F, Camargo-Ramírez R, et al. A novel Transposable element-derived microRNA participates in plant immunity to rice blast disease [J]. Plant Biotechnol J, 2021, 19(9): 1798-1811.
[36]	Wang H, Li Y, Chern M, et al. Suppression of rice miR168 improves yield, flowering time and immunity [J]. Nat Plants, 2021, 7(2): 129-136.
[37]	Zhao BT, Liang RQ, Ge LF, et al. Identification of drought-induced microRNAs in rice [J]. Biochem Biophys Res Commun, 2007, 354(2): 585-590.
[38]	Zhao BT, Ge LF, Liang RQ, et al. Members of miR-169 family are induced by high salinity and transiently inhibit the NF-YA transcription factor [J]. BMC Mol Biol, 2009, 10: 29.
[39]	Li Y, Zhao SL, Li JL, et al. Osa-miR169 negatively regulates rice immunity against the blast fungus Magnaporthe oryzae [J]. Front Plant Sci, 2017, 8: 2.
[1]	Zhan JP, Meyers BC. Plant small RNAs: their biogenesis, regulatory roles, and functions [J]. Annu Rev Plant Biol, 2023, 74: 21-51.
[2]	Wang JL, Mei J, Ren GD. Plant microRNAs: biogenesis, homeostasis, and degradation [J]. Front Plant Sci, 2019, 10: 360.
[3]	Xie DQ, Chen M, Niu JR, et al. Phase separation of SERRATE drives dicing body assembly and promotes miRNA processing in Arabidopsis [J]. Nat Cell Biol, 2021, 23(1): 32-39.
[4]	Mi SJ, Cai T, Hu YG, et al. Sorting of small RNAs into Arabidopsis argonaute complexes is directed by the 5' terminal nucleotide [J]. Cell, 2008, 133(1): 116-127.
[5]	Hutvagner G, Simard MJ. Argonaute proteins: key players in RNA silencing [J]. Nat Rev Mol Cell Biol, 2008, 9(1): 22-32.
[6]	Jiang JJ, Zhu HT, Li N, et al. The miR393-target module regulates plant development and responses to biotic and abiotic stresses [J]. Int J Mol Sci, 2022, 23(16): 9477.
[7]	Jing WK, Gong FF, Liu GQ, et al. Petal size is controlled by the MYB73/TPL/HDA19-miR159-CKX6 module regulating cytokinin catabolism in Rosa hybrida [J]. Nat Commun, 2023, 14(1): 7106.
[8]	Li YY, Liu Y, Gao ZH, et al. microRNA162 regulates stomatal conductance in response to low night temperature stress via abscisic acid signaling pathway in tomato [J]. Front Plant Sci, 2023, 14: 1045112.
[9]	Pawłasek N, Sokołowska A, Koter M, et al. The interaction between miR165/166 and miR160 regulates Arabidopsis thaliana seed size, weight, and number in a ROS-dependent manner [J]. Planta, 2024, 260(3): 72.
[10]	李有志, 方继朝. 水稻害虫: 研究进展与展望 [J]. 昆虫学报, 2024, 67(4): 443-455.
	Li YZ, Fang JC. Rice pests: research progresses and prospects [J]. Acta Entomol Sin, 2024, 67(4): 443-455.
[11]	刘万才, 刘振东, 黄冲, 等. 近10年农作物主要病虫害发生危害情况的统计和分析 [J]. 植物保护, 2016, 42(5): 1-9, 46.
	Liu WC, Liu ZD, Huang C, et al. Statistics and analysis of crop yield losses caused by main diseases and insect pests in recent 10 years [J]. Plant Prot, 2016, 42(5): 1-9, 46.
[40]	Wang ZY, Xia YQ, Lin SY, et al. Osa-miR164a targets OsNAC60 and negatively regulates rice immunity against the blast fungus Magnaporthe oryzae [J]. Plant J, 2018, 95(4): 584-597.
[41]	Zhang X, Bao YL, Shan DQ, et al. Magnaporthe oryzae induces the expression of a microRNA to suppress the immune response in rice [J]. Plant Physiol, 2018, 177(1): 352-368.
[42]	Zhao ZX, Feng Q, Cao XL, et al. Osa-miR167d facilitates infection of Magnaporthe oryzae in rice [J]. J Integr Plant Biol, 2020, 62(5): 702-715.
[43]	Gao S, Hou Y, Huang QW, et al. Osa-miR11117 targets OsPAO4 to regulate rice immunity against the blast fungus Magnaporthe oryzae [J]. Int J Mol Sci, 2023, 24(22): 16052.
[44]	Guo RZ, Zhang Q, Ying YH, et al. Functional characterization of the three Oryza sativa SPX-MFS proteins in maintaining phosphate homoeostasis [J]. Plant Cell Environ, 2023, 46(4): 1264-1277.
[45]	Campos-Soriano L, Bundó M, Bach-Pages M, et al. Phosphate excess increases susceptibility to pathogen infection in rice [J]. Mol Plant Pathol, 2020, 21(4): 555-570.
[46]	Bundó M, Val-Torregrosa B, Martín-Cardoso H, et al. Silencing Osa-miR827 via CRISPR/Cas9 protects rice against the blast fungus Magnaporthe oryzae [J]. Plant Mol Biol, 2024, 114(5): 105.
[47]	Nelson R, Wiesner-Hanks T, Wisser R, et al. Navigating complexity to breed disease-resistant crops [J]. Nat Rev Genet, 2018, 19(1): 21-33.
[48]	Wang J, Zhou L, Shi H, et al. A single transcription factor promotes both yield and immunity in rice [J]. Science, 2018, 361(6406): 1026-1028.
[49]	Jiao YQ, Wang YH, Xue DW, et al. Regulation of OsSPL14 by OsmiR156 defines ideal plant architecture in rice [J]. Nat Genet, 2010, 42(6): 541-544.
[50]	Chandran V, Wang H, Gao F, et al. miR396- OsGRF s module balances growth and rice blast disease-resistance [J]. Front Plant Sci, 2019, 9: 1999.
[51]	Zhou SX, Zhu Y, Wang LF, et al. Osa-miR1873 fine-tunes rice immunity against Magnaporthe oryzae and yield traits [J]. J Integr Plant Biol, 2020, 62(8): 1213-1226.
[52]	Li Y, Li TT, He XR, et al. Blocking Osa-miR1871 enhances rice resistance against Magnaporthe oryzae and yield [J]. Plant Biotechnol J, 2022, 20(4): 646-659.
[53]	Li Y, Zheng YP, Zhou XH, et al. Rice miR1432 fine-tunes the balance of yield and blast disease resistance via different modules [J]. Rice, 2021, 14(1): 87.
[54]	Zhao YF, Peng T, Sun HZ, et al. miR1432-OsACOT (Acyl-CoA thioesterase) module determines grain yield via enhancing grain filling rate in rice [J]. Plant Biotechnol J, 2019, 17(4): 712-723.
[55]	Li Y, Wang LF, Bhutto SH, et al. Blocking miR530 improves rice resistance, yield, and maturity [J]. Front Plant Sci, 2021, 12: 729560.
[56]	Sun W, Xu XH, Li YP, et al. OsmiR530 acts downstream of OsPIL15 to regulate grain yield in rice [J]. New Phytol, 2020, 226(3): 823-837.
[57]	Li YF, Zheng Y, Addo-Quaye C, et al. Transcriptome-wide identification of microRNA targets in rice [J]. Plant J, 2010, 62(5): 742-759.
[58]	Zhang LL, Huang YY, Zheng YP, et al. Osa-miR535 targets SQUAMOSA promoter binding protein-like 4 to regulate blast disease resistance in rice [J]. Plant J, 2022, 110(1): 166-178.
[59]	Fu J, Liu HB, Li Y, et al. Manipulating broad-spectrum disease resistance by suppressing pathogen-induced auxin accumulation in rice [J]. Plant Physiol, 2011, 155(1): 589-602.
[60]	Yu C, Chen YT, Cao YQ, et al. Overexpression of miR169o, an overlapping microRNA in response to both nitrogen limitation and bacterial infection, promotes nitrogen use efficiency and susceptibility to bacterial blight in rice [J]. Plant Cell Physiol, 2018, 59(6): 1234-1247.
[61]	Liu MM, Shi ZY, Zhang XH, et al. Inducible overexpression of Ideal Plant Architecture1 improves both yield and disease resistance in rice [J]. Nat Plants, 2019, 5(4): 389-400.
[62]	Jia YF, Li QL, Li YY, et al. Inducible enrichment of Osa-miR1432 confers rice bacterial blight resistance through suppressing OsCaML2 [J]. Int J Mol Sci, 2021, 22(21): 11367.
[63]	Moscou MJ, Bogdanove AJ. A simple cipher governs DNA recognition by TAL effectors [J]. Science, 2009, 326(5959): 1501.
[64]	Molla KA, Karmakar S, Molla J, et al. Understanding sheath blight resistance in rice: the road behind and the road ahead [J]. Plant Biotechnol J, 2020, 18(4): 895-915.
[65]	Feng T, Zhang ZY, Gao P, et al. Suppression of rice Osa-miR444.2 improves the resistance to sheath blight in rice mediating through the phytohormone pathway [J]. Int J Mol Sci, 2023, 24(4): 3653.
[66]	Wu JG, Yang GY, Zhao SS, et al. Current rice production is highly vulnerable to insect-borne viral diseases [J]. Natl Sci Rev, 2022, 9(9): nwac131.
[67]	Wu JG, Yang RX, Yang ZR, et al. ROS accumulation and antiviral defence control by microRNA528 in rice [J]. Nat Plants, 2017, 3: 16203.
[68]	Wu JG, Yang ZR, Wang Y, et al. Viral-inducible Argonaute18 confers broad-spectrum virus resistance in rice by sequestering a host microRNA [J]. eLife, 2015, 4: e05733.
[69]	Yao SZ, Yang ZR, Yang RX, et al. Transcriptional regulation of miR528 by OsSPL9 orchestrates antiviral response in rice [J]. Mol Plant, 2019, 12(8): 1114-1122.
[70]	Wang NN, Zhang D, Wang ZH, et al. Mutation of the RDR1 gene caused genome-wide changes in gene expression, regional variation in small RNA clusters and localized alteration in DNA methylation in rice [J]. BMC Plant Biol, 2014, 14: 177.
[71]	Wang HC, Jiao XM, Kong XY, et al. A signaling cascade from miR444 to RDR1 in rice antiviral RNA silencing pathway [J]. Plant Physiol, 2016, 170(4): 2365-2377.
[72]	Tong AZ, Yuan Q, Wang S, et al. Altered accumulation of Osa-miR171b contributes to rice stripe virus infection by regulating disease symptoms [J]. J Exp Bot, 2017, 68(15): 4357-4367.
[73]	Zhang C, Ding ZM, Wu KC, et al. Suppression of jasmonic acid-mediated defense by viral-inducible microRNA319 facilitates virus infection in rice [J]. Mol Plant, 2016, 9(9): 1302-1314.
[74]	Liu YQ, Wu H, Chen H, et al. A gene cluster encoding lectin receptor kinases confers broad-spectrum and durable insect resistance in rice [J]. Nat Biotechnol, 2015, 33(3): 301-305.
[75]	Guo JP, Xu CX, Wu D, et al. Bph6 encodes an exocyst-localized protein and confers broad resistance to planthoppers in rice [J]. Nat Genet, 2018, 50(2): 297-306.
[12]	杨婕, 杨长登, 曾宇翔, 等. 水稻稻瘟病抗性基因挖掘与利用研究进展[J]. 中国水稻科学, 2024, 38(6): 591-603.
	Yang J, Yang CD, Zeng YX, et al. Research progress in mining and utilization of rice blast resistance genes [J]. Chin J Rice Sci, 2024, 38(6): 591-603.
[13]	Zhou B, Qu SH, Liu GF, et al. The eight amino-acid differences within three leucine-rich repeats between Pi2 and Piz-t resistance proteins determine the resistance specificity to Magnaporthe grisea [J]. Mol Plant Microbe Interact, 2006, 19(11): 1216-1228.
[14]	Deng YW, Zhu XD, Shen Y, et al. Genetic characterization and fine mapping of the blast resistance locus Pigm(t) tightly linked to Pi2 and Pi9 in a broad-spectrum resistant Chinese variety [J]. Theor Appl Genet, 2006, 113(4): 705-713.
[15]	Javed M, Reddy B, Sheoran N, et al. Unraveling the transcriptional network regulated by miRNAs in blast-resistant and blast-susceptible rice genotypes during Magnaporthe oryzae interaction [J]. Gene, 2023, 886: 147718.
[76]	Zhao Y, Huang J, Wang ZZ, et al. Allelic diversity in an NLR gene BPH9 enables rice to combat planthopper variation [J]. Proc Natl Acad Sci USA, 2016, 113(45): 12850-12855.
[77]	Shi SJ, Wang HY, Nie LY, et al. Bph30 confers resistance to brown planthopper by fortifying sclerenchyma in rice leaf sheaths [J]. Mol Plant, 2021, 14(10): 1714-1732.
[78]	Ge YF, Han JY, Zhou GX, et al. Silencing of miR156 confers enhanced resistance to brown planthopper in rice [J]. Planta, 2018, 248(4): 813-826.
[79]	Li R, Zhang J, Li JC, et al. Prioritizing plant defence over growth through WRKY regulation facilitates infestation by non-target herbivores [J]. eLife, 2015, 4: e04805.
[80]	Dai ZY, Tan J, Zhou C, et al. The OsmiR396-OsGRF8-OsF3H-flavonoid pathway mediates resistance to the brown planthopper in rice (Oryza sativa) [J]. Plant Biotechnol J, 2019, 17(8): 1657-1669.
[81]	Chen S, Sun B, Shi ZY, et al. Identification of the rice genes and metabolites involved in dual resistance against brown planthopper and rice blast fungus [J]. Plant Cell Environ, 2022, 45(6): 1914-1929.
[82]	Shen YJ, Yang GQ, Miao XX, et al. OsmiR159 modulate BPH resistance through regulating G-protein γ subunit GS3 gene in rice [J]. Rice, 2023, 16(1): 30.
[83]	Fan CC, Xing YZ, Mao HL, et al. GS3, a major QTL for grain length and weight and minor QTL for grain width and thickness in rice, encodes a putative transmembrane protein [J]. Theor Appl Genet, 2006, 112(6): 1164-1171.
[84]	Chen J, Liu Q, Yuan LY, et al. Osa-miR162a enhances the resistance to the brown planthopper via α-linolenic acid metabolism in rice (Oryza sativa) [J]. J Agric Food Chem, 2023, 71(31): 11847-11859.
[85]	Sun B, Shen YJ, Zhu L, et al. OsmiR319-OsPCF5 modulate resistance to brown planthopper in rice through association with MYB proteins [J]. BMC Biol, 2024, 22(1): 68.
[86]	He J, Liu YQ, Yuan DY, et al. An R2R3 MYB transcription factor confers brown planthopper resistance by regulating the phenylalanine ammonia-lyase pathway in rice [J]. Proc Natl Acad Sci USA, 2020, 117(1): 271-277.
[87]	Sun B, Shen YJ, Chen S, et al. A novel transcriptional repressor complex MYB22-TOPLESS-HDAC1 promotes rice resistance to brown planthopper by repressing F3'H expression [J]. New Phytol, 2023, 239(2): 720-738.
[88]	Boller T, He SY. Innate immunity in plants: an arms race between pattern recognition receptors in plants and effectors in microbial pathogens [J]. Science, 2009, 324(5928): 742-744.
[89]	Boller T, Felix G. A renaissance of elicitors: perception of microbe-associated molecular patterns and danger signals by pattern-recognition receptors [J]. Annu Rev Plant Biol, 2009, 60: 379-406.
[90]	Zhang ZL, Wang XJ, Lu JB, et al. Cross-Kingdom RNA interference mediated by insect salivary microRNAs may suppress plant immunity [J]. Proc Natl Acad Sci USA, 2024, 121(16): e2318783121.