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NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle

Author

Listed:
  • Tatsiana Kosciuk

    (Cornell University)

  • Ian R. Price

    (Cornell University)

  • Xiaoyu Zhang

    (Cornell University)

  • Chengliang Zhu

    (Cornell University)

  • Kayla N. Johnson

    (Cornell University)

  • Shuai Zhang

    (Cornell University
    Cornell University)

  • Steve L. Halaby

    (Cornell University)

  • Garrison P. Komaniecki

    (Cornell University)

  • Min Yang

    (Cornell University)

  • Caroline J. DeHart

    (Northwestern University)

  • Paul M. Thomas

    (Northwestern University)

  • Neil L. Kelleher

    (Northwestern University)

  • J. Christopher Fromme

    (Cornell University)

  • Hening Lin

    (Cornell University
    Cornell University)

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.

Suggested Citation

  • Tatsiana Kosciuk & Ian R. Price & Xiaoyu Zhang & Chengliang Zhu & Kayla N. Johnson & Shuai Zhang & Steve L. Halaby & Garrison P. Komaniecki & Min Yang & Caroline J. DeHart & Paul M. Thomas & Neil L. K, 2020. "NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14893-x
    DOI: 10.1038/s41467-020-14893-x
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    Cited by:

    1. Miao Wang & Yugang Zhang & Garrison P. Komaniecki & Xuan Lu & Ji Cao & Mingming Zhang & Tao Yu & Dan Hou & Nicole A. Spiegelman & Ming Yang & Ian R. Price & Hening Lin, 2022. "Golgi stress induces SIRT2 to counteract Shigella infection via defatty-acylation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Diego Rodríguez-Hernández & Kamalakannan Vijayan & Rachael Zigweid & Michael K. Fenwick & Banumathi Sankaran & Wanlapa Roobsoong & Jetsumon Sattabongkot & Elizabeth K. K. Glennon & Peter J. Myler & Pe, 2023. "Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Zhirui Cao & Dejun Fan & Yang Sun & Ziyu Huang & Yue Li & Runping Su & Feng Zhang & Qing Li & Hongju Yang & Fen Zhang & Yinglei Miao & Ping Lan & Xiaojian Wu & Tao Zuo, 2024. "The gut ileal mucosal virome is disturbed in patients with Crohn’s disease and exacerbates intestinal inflammation in mice," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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