細胞膜的完整性對於維持細胞的生理功能，例如：胞內平衡與抵抗病原體，是非常重要的。細菌穿孔毒素是多種病原體在感染及傳播過程中重要的毒理因子，其透過在宿主細胞膜上形成孔洞來破壞細胞膜的完整性。然而，關於宿主細胞如何對抗細菌穿孔毒素並維持細胞膜完整性的防禦策略目前仍不明確。在我們之前的研究中顯示，線蟲在遭遇細菌穿孔毒素時，會啟動由轉錄因子HLH-30/TFEB介導的細胞自我防禦系統，並透過啟動細胞自噬作用和修復腸上皮細胞膜穿孔之機制，以抵禦此毒素造成的傷害。目前的研究中，已知轉錄因子 HLH-30/TFEB在非常多生理功能中，包括溶酶體生合成、活化細胞自噬作用與代謝調節方面，都扮演舉足輕重的角色，因而需要被嚴格地調控。然而，HLH-30/TFEB如何被細菌穿孔毒素刺激、活化的分子機制目前仍缺乏深入探討。在本研究中，我們揭露了在秀麗隱桿線蟲中，蛋白質精氨酸甲基轉移酶-7（protein arginine methyltransferase-7, PRMT-7）在活化HLH-30及後續的細胞自我防禦啟動中的關鍵作用。我們利用蛋白質質譜分析和遺傳學分析證明了PRMT-7會對於HLH-30與RAGA-1 GTPase結合區中的精氨酸進行甲基化，此精氨酸的甲基化修飾將阻斷HLH-30與RAGA-1 GTPase之結合，進而破壞了LET-363/MTOR介導的磷酸化並促進HLH-30入核。除此之外，宿主對細菌穿孔毒素的這種防禦機制具有演化保守性。在人類腸上皮細胞中，PRMT7也具有調節TFEB在細胞中分佈的能力並且參與修復細菌穿孔毒素導致的腸細胞膜穿孔。我們的研究不僅揭示了由PRMT-7/PRMT7介導之全新的HLH-30/TFEB轉譯後調控，對於細胞自我防禦系統抵禦細菌穿孔毒素這項機制在後生動物中的保守性也有了更進一步的洞察。

Plasma membrane integrity (PMI) is vital for maintaining cellular homeostasis and functions in pathogens defense. Bacterial pore-forming toxins (PFTs), which perforate plasma membrane, serve as significant virulence factors for a variety of pathogens during infection. However, the strategies by which host cells ward against bacterial PFTs intoxication and preserve PMI remain ambiguous. In our prior study, we demonstrated the HLH-30/TFEB-dependent intrinsic cellular defense (INCED) system, including autophagy and perforation repairing in the intestinal epithelium cells, is activated in response to bacterial PFT intoxication in Caenorhabditis elegans. The transcription factor HLH-30/TFEB, which is characterized as fundamental in various physiological functions, including lysosomal biogenesis, autophagy activation and metabolism regulation, requires stringent regulation. However, the molecular mechanism underlying HLH-30/TFEB activation in response to PFTs remains understudied. Here, we unveil the essential role of protein arginine methyltransferase-7 (PRMT-7) in HLH-30 activation and the subsequent INCED in C. elegans. Our mass spectrometry and genetic analyses demonstrated that PRMT-7 mediates the methylation of HLH-30 within its RRAGA GTPase binding domain, disrupting LET-363/MTOR-dependent phosphorylation and promoting HLH-30 nuclear localization. Furthermore, this host response against PFTs is evolutionarily conserved. PRMT7 regulates TFEB cellular distribution and repairs perforations induced by bacterial PFTs in human intestinal epithelial cells. Our findings not only reveal a novel post-translational regulation of HLH-30/TFEB by PRMT-7/PRMT7 but also provide further insights into the evolutionary conserveness of INCED against PFT intoxication in metazoans.

1. Suda K, Moriyama Y, Razali N, Chiu Y, Masukagami Y, Nishimura K, et al. Plasma membrane damage limits replicative lifespan in yeast and induces premature senescence in human fibroblasts. Nature Aging. 2024;4(3):319-35.
2. Dias C, Nylandsted J. Plasma membrane integrity in health and disease: significance and therapeutic potential. Cell Discov. 2021;7(1):4.
3. Andrews NW, Corrotte M. Plasma membrane repair. Current Biology. 2018;28(8):R392-R7.
4. Dias C, Nylandsted J. Plasma membrane integrity in health and disease: significance and therapeutic potential. Cell Discovery. 2021;7(1):4.
5. Reddy A, Caler EV, Andrews NW. Plasma Membrane Repair Is Mediated by Ca2+-Regulated Exocytosis of Lysosomes. Cell. 2001;106(2):157-69.
6. Appelqvist H, Wäster P, Kågedal K, Öllinger K. The lysosome: from waste bag to potential therapeutic target. Journal of Molecular Cell Biology. 2013;5(4):214-26.
7. Tam C, Idone V, Devlin C, Fernandes MC, Flannery A, He X, et al. Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. J Cell Biol. 2010;189(6):1027-38.
8. Ammendolia DA, Bement WM, Brumell JH. Plasma membrane integrity: implications for health and disease. BMC Biology. 2021;19(1):71.
9. Zhen Y, Radulovic M, Vietri M, Stenmark H. Sealing holes in cellular membranes. EMBO J. 2021;40(7):e106922.
10. Barisch C, Holthuis JCM, Cosentino K. Membrane damage and repair: a thin line between life and death. Biol Chem. 2023;404(5):467-90.
11. Brito C, Cabanes D, Sarmento Mesquita F, Sousa S. Mechanisms protecting host cells against bacterial pore-forming toxins. Cellular and Molecular Life Sciences. 2019;76(7):1319-39.
12. Gonzalez MR, Bischofberger M, Frêche B, Ho S, Parton RG, van der Goot FG. Pore-forming toxins induce multiple cellular responses promoting survival. Cellular Microbiology. 2011;13(7):1026-43.
13. Gouaux E. Channel-forming toxins: tales of transformation. Curr Opin Struct Biol. 1997;7(4):566-73.
14. Iacovache I, Bischofberger M, van der Goot FG. Structure and assembly of pore-forming proteins. Current Opinion in Structural Biology. 2010;20(2):241-6.
15. Lesieur C, Vécsey-Semjén B, Abrami L, Fivaz M, Gisou van der Goot F. Membrane insertion: The strategies of toxins (review). Mol Membr Biol. 1997;14(2):45-64.
16. Los FCO, Randis TM, Aroian RV, Ratner AJ. Role of Pore-Forming Toxins in Bacterial Infectious Diseases. Microbiology and Molecular Biology Reviews. 2013;77(2):173-207.
17. Peraro MD, van der Goot FG. Pore-forming toxins: ancient, but never really out of fashion. Nature Reviews Microbiology. 2016;14(2):77-92.
18. Brouwer S, Rivera-Hernandez T, Curren BF, Harbison-Price N, De Oliveira DMP, Jespersen MG, et al. Pathogenesis, epidemiology and control of Group A Streptococcus infection. Nature Reviews Microbiology. 2023;21(7):431-47.
19. Draberova L, Tumova M, Draber P. Molecular Mechanisms of Mast Cell Activation by Cholesterol-Dependent Cytolysins. Front Immunol. 2021;12:670205.
20. Chen PL, Lamy B, Ko WC. Aeromonas dhakensis, an Increasingly Recognized Human Pathogen. Front Microbiol. 2016;7:793.
21. Su Y-C, Wang C-C, Chen Y-W, Wang S-T, Shu C-Y, Tsai P-J, et al. Haemolysin Ahh1 secreted from Aeromonas dhakensis activates the NLRP3 inflammasome in macrophages and mediates severe soft tissue infection. International Immunopharmacology. 2024;128:111478.
22. Chen YW, Yeh WH, Tang HJ, Chen JW, Shu HY, Su YC, et al. UvrY is required for the full virulence of Aeromonas dhakensis. Virulence. 2020;11(1):502-20.
23. Chen M-C. Investigating the mechanism of PRMT-7 mdiated Rag complex-HLH-30/TFEB interaction upon bacterial pore-forming toxin intoxication: National Cheng Kung University; 2022.
24. de Maagd RA, Bravo A, Crickmore N. How Bacillus thuringiensis has evolved specific toxins to colonize the insect world. Trends Genet. 2001;17(4):193-9.
25. Beegle CC, Yamamoto T. INVITATION PAPER (C.P. ALEXANDER FUND): HISTORY OF BACILLUS THURINGIENSIS BERLINER RESEARCH AND DEVELOPMENT. The Canadian Entomologist. 1992;124(4):587-616.
26. Nester EW, Thomashow LS, Metz M, Gordon M. American Academy of Microbiology Colloquia Reports. 100 Years of Bacillus thuringiensis: A Critical Scientific Assessment: This report is based on a colloquium, “100 Years of Bacillis thuringiensis, a Paradigm for Producing Transgenic Organisms: A Critical Scientific Assessment,” sponsored by the American Academy of Microbiology and held November 16–18, in Ithaca, New York. Washington (DC): American Society for Microbiology
Copyright 2002 American Academy of Microbiology.; 2002.
27. Marroquin LD, Elyassnia D, Griffitts JS, Feitelson JS, Aroian RV. Bacillus thuringiensis (Bt) toxin susceptibility and isolation of resistance mutants in the nematode Caenorhabditis elegans. Genetics. 2000;155(4):1693-9.
28. Wei JZ, Hale K, Carta L, Platzer E, Wong C, Fang SC, Aroian RV. Bacillus thuringiensis crystal proteins that target nematodes. Proc Natl Acad Sci U S A. 2003;100(5):2760-5.
29. Griffitts JS, Huffman DL, Whitacre JL, Barrows BD, Marroquin LD, Müller R, et al. Resistance to a Bacterial Toxin Is Mediated by Removal of a Conserved Glycosylation Pathway Required for Toxin-Host Interactions*. Journal of Biological Chemistry. 2003;278(46):45594-602.
30. Griffitts JS, Whitacre JL, Stevens DE, Aroian RV. Bt toxin resistance from loss of a putative carbohydrate-modifying enzyme. Science. 2001;293(5531):860-4.
31. Griffitts JS, Haslam SM, Yang T, Garczynski SF, Mulloy B, Morris H, et al. Glycolipids as Receptors for <i>Bacillus thuringiensis</i> Crystal Toxin. Science. 2005;307(5711):922-5.
32. García-Montelongo M, González-Villarreal SE, Del Rincón-Castro MC, Ibarra JE. Use of RNAi as a preliminary tool for screening putative receptors of nematicidal toxins from Bacillus thuringiensis. Archives of Microbiology. 2021;203(4):1649-56.
33. Chen HD, Kao CY, Liu BY, Huang SW, Kuo CJ, Ruan JW, et al. HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans. Autophagy. 2017;13(2):371-85.
34. Napolitano G, Ballabio A. TFEB at a glance. Journal of Cell Science. 2016;129(13):2475-81.
35. Tan A, Prasad R, Lee C, Jho E-h. Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease. Cell Death & Differentiation. 2022;29(8):1433-49.
36. Martina JA, Puertollano R. Rag GTPases mediate amino acid-dependent recruitment of TFEB and MITF to lysosomes. J Cell Biol. 2013;200(4):475-91.
37. Cui Z, Napolitano G, de Araujo MEG, Esposito A, Monfregola J, Huber LA, et al. Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex. Nature. 2023;614(7948):572-9.
38. Martina JA, Chen Y, Gucek M, Puertollano R. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy. 2012;8(6):903-14.
39. Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Erdin S, et al. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. Embo j. 2012;31(5):1095-108.
40. Vega-Rubin-de-Celis S, Peña-Llopis S, Konda M, Brugarolas J. Multistep regulation of TFEB by MTORC1. Autophagy. 2017;13(3):464-72.
41. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, et al. TFEB links autophagy to lysosomal biogenesis. Science. 2011;332(6036):1429-33.
42. Li Y, Xu M, Ding X, Yan C, Song Z, Chen L, et al. Protein kinase C controls lysosome biogenesis independently of mTORC1. Nat Cell Biol. 2016;18(10):1065-77.
43. Creamer TP. Calcineurin. Cell Commun Signal. 2020;18(1):137.
44. Puertollano R, Ferguson SM, Brugarolas J, Ballabio A. The complex relationship between TFEB transcription factor phosphorylation and subcellular localization. The EMBO Journal. 2018;37(11):e98804.
45. Sha Y, Rao L, Settembre C, Ballabio A, Eissa NT. STUB1 regulates TFEB-induced autophagy-lysosome pathway. Embo j. 2017;36(17):2544-52.
46. Martina JA, Guerrero‐Gómez D, Gómez‐Orte E, Antonio Bárcena J, Cabello J, Miranda‐Vizuete A, Puertollano R. A conserved cysteine‐based redox mechanism sustains TFEB/HLH‐30 activity under persistent stress. The EMBO Journal. 2021;40(3):e105793.
47. Guo A, Gu H, Zhou J, Mulhern D, Wang Y, Lee KA, et al. Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol Cell Proteomics. 2014;13(1):372-87.
48. McBride AE, Zurita-Lopez C, Regis A, Blum E, Conboy A, Elf S, Clarke S. Protein arginine methylation in Candida albicans: role in nuclear transport. Eukaryot Cell. 2007;6(7):1119-29.
49. La Spina M, Contreras PS, Rissone A, Meena NK, Jeong E, Martina JA. MiT/TFE Family of Transcription Factors: An Evolutionary Perspective. Front Cell Dev Biol. 2020;8:609683.
50. Kuo CJ, Hansen M, Troemel E. Autophagy and innate immunity: Insights from invertebrate model organisms. Autophagy. 2018;14(2):233-42.
51. Irazoqui JE, Urbach JM, Ausubel FM. Evolution of host innate defence: insights from Caenorhabditis elegans and primitive invertebrates. Nature Reviews Immunology. 2010;10(1):47-58.
52. Leiser SF, Miller H, Rossner R, Fletcher M, Leonard A, Primitivo M, et al. Cell nonautonomous activation of flavin-containing monooxygenase promotes longevity and health span. Science. 2015;350(6266):1375-8.
53. Kumsta C, Chang JT, Schmalz J, Hansen M. Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans. Nat Commun. 2017;8:14337.
54. Mansueto G, Armani A, Viscomi C, D'Orsi L, De Cegli R, Polishchuk EV, et al. Transcription Factor EB Controls Metabolic Flexibility during Exercise. Cell Metab. 2017;25(1):182-96.
55. Palikaras K, Mari M, Petanidou B, Pasparaki A, Filippidis G, Tavernarakis N. Ectopic fat deposition contributes to age-associated pathology in Caenorhabditis elegans. J Lipid Res. 2017;58(1):72-80.
56. Murphy JT, Liu H, Ma X, Shaver A, Egan BM, Oh C, et al. Simple nutrients bypass the requirement for HLH-30 in coupling lysosomal nutrient sensing to survival. PLoS Biol. 2019;17(5):e3000245.
57. Bedford MT, Clarke SG. Protein Arginine Methylation in Mammals: Who, What, and Why. Molecular Cell. 2009;33(1):1-13.
58. Gao Y, Feng C, Ma J, Yan Q. Protein arginine methyltransferases (PRMTs): Orchestrators of cancer pathogenesis, immunotherapy dynamics, and drug resistance. Biochemical Pharmacology. 2024;221:116048.
59. Rakow S, Pullamsetti SS, Bauer U-M, Bouchard C. Assaying epigenome functions of PRMTs and their substrates. Methods. 2020;175:53-65.
60. Yang Y, Bedford MT. Protein arginine methyltransferases and cancer. Nature Reviews Cancer. 2013;13(1):37-50.
61. Tewary SK, Zheng YG, Ho MC. Protein arginine methyltransferases: insights into the enzyme structure and mechanism at the atomic level. Cell Mol Life Sci. 2019;76(15):2917-32.
62. Blanc RS, Richard S. Arginine Methylation: The Coming of Age. Mol Cell. 2017;65(1):8-24.
63. Butler JS, Zurita-Lopez CI, Clarke SG, Bedford MT, Dent SYR. Protein-arginine Methyltransferase 1 (PRMT1) Methylates Ash2L, a Shared Component of Mammalian Histone H3K4 Methyltransferase Complexes*. Journal of Biological Chemistry. 2011;286(14):12234-44.
64. Meister G, Eggert C, Bühler D, Brahms H, Kambach C, Fischer U. Methylation of Sm proteins by a complex containing PRMT5 and the putative U snRNP assembly factor pICln. Current Biology. 2001;11(24):1990-4.
65. Bezzi M, Teo SX, Muller J, Mok WC, Sahu SK, Vardy LA, et al. Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery. Genes Dev. 2013;27(17):1903-16.
66. Yang Y, Hadjikyriacou A, Xia Z, Gayatri S, Kim D, Zurita-Lopez C, et al. PRMT9 is a Type II methyltransferase that methylates the splicing factor SAP145. Nature Communications. 2015;6(1):6428.
67. Feng Y, Maity R, Whitelegge JP, Hadjikyriacou A, Li Z, Zurita-Lopez C, et al. Mammalian protein arginine methyltransferase 7 (PRMT7) specifically targets RXR sites in lysine- and arginine-rich regions. J Biol Chem. 2013;288(52):37010-25.
68. Feng Y, Hadjikyriacou A, Clarke S. Substrate Specificity of Human Protein Arginine Methyltransferase 7 (PRMT7): The Importance of Acidic Residues in the Double E Loop. The Journal of biological chemistry. 2014;289.
69. Jain K, Clarke SG. PRMT7 as a unique member of the protein arginine methyltransferase family: A review. Arch Biochem Biophys. 2019;665:36-45.
70. Blanc Roméo S, Vogel G, Chen T, Crist C, Richard S. PRMT7 Preserves Satellite Cell Regenerative Capacity. Cell Reports. 2016;14(6):1528-39.
71. Yao R, Jiang H, Ma Y, Wang L, Wang L, Du J, et al. PRMT7 induces epithelial-to-mesenchymal transition and promotes metastasis in breast cancer. Cancer Res. 2014;74(19):5656-67.
72. Jain K, Jin CY, Clarke SG. Epigenetic control via allosteric regulation of mammalian protein arginine methyltransferases. Proceedings of the National Academy of Sciences. 2017;114(38):10101-6.
73. Gonsalvez GB, Tian L, Ospina JK, Boisvert Fo-M, Lamond AI, Matera AG. Two distinct arginine methyltransferases are required for biogenesis of Sm-class ribonucleoproteins. Journal of Cell Biology. 2007;178(5):733-40.
74. Hadjikyriacou A, Clarke SG. Caenorhabditis elegans PRMT-7 and PRMT-9 Are Evolutionarily Conserved Protein Arginine Methyltransferases with Distinct Substrate Specificities. Biochemistry. 2017;56(20):2612-26.
75. Brenner S. Genetics of Caenorhabditis-Elegans. Genetics. 1974;77(1):71-94.
76. Bischof LJ, Huffman DL, Aroian RV. Assays for toxicity studies in C. elegans with Bt crystal proteins. Methods Mol Biol. 2006;351:139-54.
77. Elangovan M, Wallrabe H, Chen Y, Day RN, Barroso M, Periasamy A. Characterization of one- and two-photon excitation fluorescence resonance energy transfer microscopy. Methods. 2003;29(1):58-73.
78. Gordon GW, Berry G, Liang XH, Levine B, Herman B. Quantitative fluorescence resonance energy transfer measurements using fluorescence microscopy. Biophys J. 1998;74(5):2702-13.
79. Xia Z, Liu Y. Reliable and global measurement of fluorescence resonance energy transfer using fluorescence microscopes. Biophys J. 2001;81(4):2395-402.
80. Youvan D, Coleman W, Silva C, Petersen J, Bylina E, Yang M. Fluorescence imaging micro-spectrophotometer (FIMS). Biotechnology et Alia. 1997;1.
81. Hsieh HC, Huang IH, Chang SW, Chen PL, Su YC, Wang S, et al. PRMT-7/PRMT7 activates HLH-30/TFEB to guard plasma membrane integrity compromised by bacterial pore-forming toxins. Autophagy. 2024:1-24.
82. Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46(W1):W296-w303.
83. Mulnaes D, Porta N, Clemens R, Apanasenko I, Reiners J, Gremer L, et al. TopModel: Template-Based Protein Structure Prediction at Low Sequence Identity Using Top-Down Consensus and Deep Neural Networks. J Chem Theory Comput. 2020;16(3):1953-67.
84. Cui Z, Napolitano G, de Araujo MEG, Esposito A, Monfregola J, Huber LA, et al. Structure of the lysosomal mTORC1–TFEB–Rag–Ragulator megacomplex. Nature. 2023;614(7948):572-9.
85. Huffman DL, Abrami L, Sasik R, Corbeil J, van der Goot FG, Aroian RV. Mitogen-activated protein kinase pathways defend against bacterial pore-forming toxins. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(30):10995-1000.
86. Tsai WJ, Lai YH, Shi YA, Hammel M, Duff AP, Whitten AE, et al. Structural basis underlying the synergism of NADase and SLO during group A Streptococcus infection. Commun Biol. 2023;6(1):124.
87. Wang YC, Li C. Evolutionarily conserved protein arginine methyltransferases in non-mammalian animal systems. FEBS J. 2012;279(6):932-45.
88. Feng Y, Hadjikyriacou A, Clarke SG. Substrate specificity of human protein arginine methyltransferase 7 (PRMT7): the importance of acidic residues in the double E loop. J Biol Chem. 2014;289(47):32604-16.
89. Zhang H, Chang JT, Guo B, Hansen M, Jia K, Kovacs AL, et al. Guidelines for monitoring autophagy in Caenorhabditis elegans. Autophagy. 2015;11(1):9-27.
90. Huang I-H. The role of prmt-7 in the bacterial pore-forming toxin-induced HLH-30 nuclear translocation in C. elegans: National Chen Kung University; 2020.
91. Lee JH, Cook JR, Yang ZH, Mirochnitchenko O, Gunderson SI, Felix AM, et al. PRMT7, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine. J Biol Chem. 2005;280(5):3656-64.
92. Lorton BM, Harijan RK, Burgos ES, Bonanno JB, Almo SC, Shechter D. A Binary Arginine Methylation Switch on Histone H3 Arginine 2 Regulates Its Interaction with WDR5. Biochemistry. 2020;59(39):3696-708.
93. Zhong XY, Yuan XM, Xu YY, Yin M, Yan WW, Zou SW, et al. CARM1 Methylates GAPDH to Regulate Glucose Metabolism and Is Suppressed in Liver Cancer. Cell Rep. 2018;24(12):3207-23.
94. Campbell M, Chang PC, Huerta S, Izumiya C, Davis R, Tepper CG, et al. Protein arginine methyltransferase 1-directed methylation of Kaposi sarcoma-associated herpesvirus latency-associated nuclear antigen. J Biol Chem. 2012;287(8):5806-18.
95. Chang S-W. The role of PRMT7 in disrupting the binding of Rag complex and TFEB in response to bacterial pore-forming toxin intoxication: National Cheng Kung University; 2024.
96. Law PJ, Timofeeva M, Fernandez-Rozadilla C, Broderick P, Studd J, Fernandez-Tajes J, et al. Association analyses identify 31 new risk loci for colorectal cancer susceptibility. Nat Commun. 2019;10(1):2154.
97. Lu Y, Kweon SS, Tanikawa C, Jia WH, Xiang YB, Cai Q, et al. Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer. Gastroenterology. 2019;156(5):1455-66.
98. Mez J, Chung J, Jun G, Kriegel J, Bourlas AP, Sherva R, et al. Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans. Alzheimers Dement. 2017;13(2):119-29.
99. Wuttke M, Li Y, Li M, Sieber KB, Feitosa MF, Gorski M, et al. A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nature Genetics. 2019;51(6):957-72.
100. Chen D, Wang Z, Zhao YG, Zheng H, Zhao H, Liu N, Zhang H. Inositol Polyphosphate Multikinase Inhibits Liquid-Liquid Phase Separation of TFEB to Negatively Regulate Autophagy Activity. Dev Cell. 2020;55(5):588-602.e7.
101. Wang B, Zhang L, Dai T, Qin Z, Lu H, Zhang L, Zhou F. Liquid–liquid phase separation in human health and diseases. Signal Transduction and Targeted Therapy. 2021;6(1):290.
102. Lee S-H, Chen T-Y, Dhar SS, Gu B, Chen K, Kim YZ, et al. A feedback loop comprising PRMT7 and miR-24-2 interplays with Oct4, Nanog, Klf4 and c-Myc to regulate stemness. Nucleic Acids Research. 2016;44(22):10603-18.
103. Yao R, Jiang H, Ma Y, Wang L, Wang L, Du J, et al. PRMT7 Induces Epithelial-to-Mesenchymal Transition and Promotes Metastasis in Breast Cancer. Cancer Research. 2014;74(19):5656-67.
104. Wu S, Kasim V, Kano MR, Tanaka S, Ohba S, Miura Y, et al. Transcription factor YY1 contributes to tumor growth by stabilizing hypoxia factor HIF-1α in a p53-independent manner. Cancer Res. 2013;73(6):1787-99.
105. Geng P, Zhang Y, Liu X, Zhang N, Liu Y, Liu X, et al. Automethylation of protein arginine methyltransferase 7 and its impact on breast cancer progression. Faseb j. 2017;31(6):2287-300.
106. Shivers RP, Pagano DJ, Kooistra T, Richardson CE, Reddy KC, Whitney JK, et al. Phosphorylation of the conserved transcription factor ATF-7 by PMK-1 p38 MAPK regulates innate immunity in Caenorhabditis elegans. PLoS Genet. 2010;6(4):e1000892.
107. Hoeven R, McCallum KC, Cruz MR, Garsin DA. Ce-Duox1/BLI-3 generated reactive oxygen species trigger protective SKN-1 activity via p38 MAPK signaling during infection in C. elegans. PLoS Pathog. 2011;7(12):e1002453.
108. Kim DH. Bacteria and the aging and longevity of Caenorhabditis elegans. Annu Rev Genet. 2013;47:233-46.
109. Hornbeck PV, Zhang B, Murray B, Kornhauser JM, Latham V, Skrzypek E. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Research. 2014;43(D1):D512-D20.
110. Guccione E, Richard S. The regulation, functions and clinical relevance of arginine methylation. Nat Rev Mol Cell Biol. 2019;20(10):642-57.
111. Xu J, Richard S. Cellular pathways influenced by protein arginine methylation: Implications for cancer. Mol Cell. 2021;81(21):4357-68.
112. Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974;77(1):71-94.
113. Sarov M, Schneider S, Pozniakovski A, Roguev A, Ernst S, Zhang Y, et al. A recombineering pipeline for functional genomics applied to Caenorhabditis elegans. Nat Methods. 2006;3(10):839-44.
114. Lapierre LR, De Magalhaes Filho CD, McQuary PR, Chu CC, Visvikis O, Chang JT, et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat Commun. 2013;4:2267.
115. Kang C, You YJ, Avery L. Dual roles of autophagy in the survival of Caenorhabditis elegans during starvation. Genes Dev. 2007;21(17):2161-71.
116. Guo B, Huang X, Zhang P, Qi L, Liang Q, Zhang X, et al. Genome-wide screen identifies signaling pathways that regulate autophagy during Caenorhabditis elegans development. EMBO Rep. 2014;15(6):705-13.
117. Mitani S. Nematode, an experimental animal in the national BioResource project. Exp Anim. 2009;58(4):351-6.
118. Timmons L, Fire A. Specific interference by ingested dsRNA. Nature. 1998;395(6705):854.
119. Senturk S, Shirole NH, Nowak DG, Corbo V, Pal D, Vaughan A, et al. Rapid and tunable method to temporally control gene editing based on conditional Cas9 stabilization. Nat Commun. 2017;8:14370.
120. Roczniak-Ferguson A, Petit CS, Froehlich F, Qian S, Ky J, Angarola B, et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci Signal. 2012;5(228):ra42.