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NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle.

Kosciuk T, Price IR, Zhang X, Zhu C, Johnson KN, Zhang S, Halaby SL, Komaniecki GP, Yang M, DeHart CJ, Thomas PM, Kelleher NL, Fromme JC, Lin H
Nat Commun 11 1067 (2020)
Cited: 33 times
EuropePMC logo PMID: 32103017

Abstract

Lysine fatty acylation in mammalian cells was discovered nearly three decades ago, yet the enzymes catalyzing it remain unknown. Unexpectedly, we find that human N-terminal glycine myristoyltransferases (NMT) 1 and 2 can efficiently myristoylate specific lysine residues. They modify ADP-ribosylation factor 6 (ARF6) on lysine 3 allowing it to remain on membranes during the GTPase cycle. We demonstrate that the NAD+-dependent deacylase SIRT2 removes the myristoyl group, and our evidence suggests that NMT prefers the GTP-bound while SIRT2 prefers the GDP-bound ARF6. This allows the lysine myrisotylation-demyristoylation cycle to couple to and promote the GTPase cycle of ARF6. Our study provides an explanation for the puzzling dissimilarity of ARF6 to other ARFs and suggests the existence of other substrates regulated by this previously unknown function of NMT. Furthermore, we identified a NMT/SIRT2-ARF6 regulatory axis, which may offer new ways to treat human diseases.

Reviews - 6pau mentioned but not cited (1)

  1. Lysine Fatty Acylation: Regulatory Enzymes, Research Tools, and Biological Function. Komaniecki G, Lin H. Front Cell Dev Biol 9 717503 (2021)


Reviews citing this publication (15)

  1. Protein N-myristoylation: functions and mechanisms in control of innate immunity. Wang B, Dai T, Sun W, Wei Y, Ren J, Zhang L, Zhang M, Zhou F. Cell Mol Immunol 18 878-888 (2021)
  2. Protein Lipidation by Palmitoylation and Myristoylation in Cancer. Fhu CW, Ali A. Front Cell Dev Biol 9 673647 (2021)
  3. Sirtuin Modulators in Cellular and Animal Models of Human Diseases. Hong JY, Lin H. Front Pharmacol 12 735044 (2021)
  4. A Not-So-Ancient Grease History: Click Chemistry and Protein Lipid Modifications. Suazo KF, Park KY, Distefano MD. Chem Rev 121 7178-7248 (2021)
  5. N-Myristoyltransferase as a Glycine and Lysine Myristoyltransferase in Cancer, Immunity, and Infections. Kosciuk T, Lin H. ACS Chem Biol 15 1747-1758 (2020)
  6. Multiple Roles of SIRT2 in Regulating Physiological and Pathological Signal Transduction. Zhu C, Dong X, Wang X, Zheng Y, Qiu J, Peng Y, Xu J, Chai Z, Liu C. Genet Res (Camb) 2022 9282484 (2022)
  7. Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications. Zhong Q, Xiao X, Qiu Y, Xu Z, Chen C, Chong B, Zhao X, Hai S, Li S, An Z, Dai L. MedComm (2020) 4 e261 (2023)
  8. Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5. Fiorentino F, Castiello C, Mai A, Rotili D. J Med Chem 65 9580-9606 (2022)
  9. A global view of the human post-translational modification landscape. Kitamura N, Galligan JJ. Biochem J 480 1241-1265 (2023)
  10. Emerging role of SIRT2 in non-small cell lung cancer. Zheng M, Hu C, Wu M, Chin YE. Oncol Lett 22 731 (2021)
  11. Substrate-selective small-molecule modulators of enzymes: Mechanisms and opportunities. Lin H. Curr Opin Chem Biol 72 102231 (2023)
  12. Cell biology of protein-lipid conjugation. Sakamaki JI, Mizushima N. Cell Struct Funct 48 99-112 (2023)
  13. Post-Translational Modifications by Lipid Metabolites during the DNA Damage Response and Their Role in Cancer. Zhu G, Zheng X, Wang Z, Xu X. Biomolecules 12 1655 (2022)
  14. The ARF GTPase regulatory network in collective invasion and metastasis. Nikolatou K, Bryant DM, Sandilands E. Biochem Soc Trans 51 1559-1569 (2023)
  15. The role of N-myristoyltransferase 1 in tumour development. Wang H, Xu X, Wang J, Qiao Y. Ann Med 55 1422-1430 (2023)

Articles citing this publication (17)

  1. Dual lysine and N-terminal acetyltransferases reveal the complexity underpinning protein acetylation. Bienvenut WV, Brünje A, Boyer JB, Mühlenbeck JS, Bernal G, Lassowskat I, Dian C, Linster E, Dinh TV, Koskela MM, Jung V, Seidel J, Schyrba LK, Ivanauskaite A, Eirich J, Hell R, Schwarzer D, Mulo P, Wirtz M, Meinnel T, Giglione C, Finkemeier I. Mol Syst Biol 16 e9464 (2020)
  2. Targeting N-myristoylation for therapy of B-cell lymphomas. Beauchamp E, Yap MC, Iyer A, Perinpanayagam MA, Gamma JM, Vincent KM, Lakshmanan M, Raju A, Tergaonkar V, Tan SY, Lim ST, Dong WF, Postovit LM, Read KD, Gray DW, Wyatt PG, Mackey JR, Berthiaume LG. Nat Commun 11 5348 (2020)
  3. ER residential chaperone GRP78 unconventionally relocalizes to the cell surface via endosomal transport. Van Krieken R, Tsai YL, Carlos AJ, Ha DP, Lee AS. Cell Mol Life Sci 78 5179-5195 (2021)
  4. Reversible lysine fatty acylation of an anchoring protein mediates adipocyte adrenergic signaling. Bagchi RA, Robinson EL, Hu T, Cao J, Hong JY, Tharp CA, Qasim H, Gavin KM, Pires da Silva J, Major JL, McConnell BK, Seto E, Lin H, McKinsey TA. Proc Natl Acad Sci U S A 119 e2119678119 (2022)
  5. Binding Affinity Determines Substrate Specificity and Enables Discovery of Substrates for N-Myristoyltransferases. Su D, Kosciuk T, Yang M, Price IR, Lin H. ACS Catal 11 14877-14883 (2021)
  6. N-Myristoylation by NMT1 Is POTEE-Dependent to Stimulate Liver Tumorigenesis via Differentially Regulating Ubiquitination of Targets. Zhu G, Wang F, Li H, Zhang X, Wu Q, Liu Y, Qian M, Guo S, Yang Y, Xue X, Sun F, Qiao Y, Pan Q. Front Oncol 11 681366 (2021)
  7. Functional Screening of Parkinson's Disease Susceptibility Genes to Identify Novel Modulators of α-Synuclein Neurotoxicity in Caenorhabditis elegans. Vozdek R, Pramstaller PP, Hicks AA. Front Aging Neurosci 14 806000 (2022)
  8. Golgi stress induces SIRT2 to counteract Shigella infection via defatty-acylation. Wang M, Zhang Y, Komaniecki GP, Lu X, Cao J, Zhang M, Yu T, Hou D, Spiegelman NA, Yang M, Price IR, Lin H. Nat Commun 13 4494 (2022)
  9. Mitochondria-targeted inhibitors of the human SIRT3 lysine deacetylase. Troelsen KS, Bæk M, Nielsen AL, Madsen AS, Rajabi N, Olsen CA. RSC Chem Biol 2 627-635 (2021)
  10. Blockade of NMT1 enzymatic activity inhibits N-myristoylation of VILIP3 protein and suppresses liver cancer progression. Tan XP, He Y, Yang J, Wei X, Fan YL, Zhang GG, Zhu YD, Li ZQ, Liao HX, Qin DJ, Guan XY, Li B. Signal Transduct Target Ther 8 14 (2023)
  11. Development of a NanoBRET assay to validate inhibitors of Sirt2-mediated lysine deacetylation and defatty-acylation that block prostate cancer cell migration. Vogelmann A, Schiedel M, Wössner N, Merz A, Herp D, Hammelmann S, Colcerasa A, Komaniecki G, Hong JY, Sum M, Metzger E, Neuwirt E, Zhang L, Einsle O, Groß O, Schüle R, Lin H, Sippl W, Jung M. RSC Chem Biol 3 468-485 (2022)
  12. Identification of and Structural Insights into Hit Compounds Targeting N-Myristoyltransferase for Cryptosporidium Drug Development. Fenwick MK, Reers AR, Liu Y, Zigweid R, Sankaran B, Shin J, Hulverson MA, Hammerson B, Fernández Álvaro E, Myler PJ, Kaushansky A, Van Voorhis WC, Fan E, Staker BL. ACS Infect Dis 9 1821-1833 (2023)
  13. Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts. Rodríguez-Hernández D, Vijayan K, Zigweid R, Fenwick MK, Sankaran B, Roobsoong W, Sattabongkot J, Glennon EKK, Myler PJ, Sunnerhagen P, Staker BL, Kaushansky A, Grøtli M. Nat Commun 14 5408 (2023)
  14. Lipids and Secretory Vesicle Exocytosis. Akefe IO, Osborne SL, Matthews B, Wallis TP, Meunier FA. Adv Neurobiol 33 357-397 (2023)
  15. Sirtuin 2 promotes human cytomegalovirus replication by regulating cell cycle progression. Betsinger CN, Justice JL, Tyl MD, Edgar JE, Budayeva HG, Abu YF, Cristea IM. mSystems 8 e0051023 (2023)
  16. Targeting N-Myristoylation Through NMT2 Prevents Cardiac Hypertrophy and Heart Failure. Tomita Y, Anzai F, Misaka T, Ogawara R, Ichimura S, Wada K, Kimishima Y, Yokokawa T, Ishida T, Takeishi Y. JACC Basic Transl Sci 8 1263-1282 (2023)
  17. The putative myristoylome of Physcomitrium patens reveals conserved features of myristoylation in basal land plants. Lai L, Ruan J, Xiao C, Yi P. Plant Cell Rep 42 1107-1124 (2023)


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