Proteolytic elimination of N-myristoyl modifications by the Shigella virulence factor IpaJ

Nikolay Burnaevskiy, Thomas G. Fox, Daniel A. Plymire, James M. Ertelt, Bethany Weigele, Andrey S. Selyunin, Sing Sing Way, Steven M. Patrie, Neal M. Alto

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Protein N-myristoylation is a 14-carbon fatty-acid modification that is conserved across eukaryotic species and occurs on nearly 1% of the cellular proteome. The ability of the myristoyl group to facilitate dynamic protein-protein and protein-membrane interactions (known as the myristoyl switch) makes it an essential feature of many signal transduction systems. Thus pathogenic strategies that facilitate protein demyristoylation would markedly alter the signalling landscape of infected host cells. Here we describe an irreversible mechanism of protein demyristoylation catalysed by invasion plasmid antigen J (IpaJ), a previously uncharacterized Shigella flexneri type III effector protein with cysteine protease activity. A yeast genetic screen for IpaJ substrates identified ADP-ribosylation factor (ARF)1p and ARF2p, small molecular mass GTPases that regulate cargo transport through the Golgi apparatus. Mass spectrometry showed that IpaJ cleaved the peptide bond between N-myristoylated glycine-2 and asparagine-3 of human ARF1, thereby providing a new mechanism for host secretory inhibition by a bacterial pathogen. We further demonstrate that IpaJ cleaves an array of N-myristoylated proteins involved in cellular growth, signal transduction, autophagasome maturation and organelle function. Taken together, these findings show a previously unrecognized pathogenic mechanism for the site-specific elimination of N-myristoyl protein modification.

Original languageEnglish (US)
Pages (from-to)106-109
Number of pages4
JournalNature
Volume496
Issue number7443
DOIs
StatePublished - Apr 4 2013
Externally publishedYes

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Shigella
Virulence Factors
Plasmids
Antigens
Proteins
Signal Transduction
ADP-Ribosylation Factors
Shigella flexneri
Cysteine Proteases
Asparagine
GTP Phosphohydrolases
Golgi Apparatus
Proteome
Organelles
Glycine
Mass Spectrometry
Membrane Proteins
Fatty Acids
Carbon
Yeasts

ASJC Scopus subject areas

  • General

Cite this

Burnaevskiy, N., Fox, T. G., Plymire, D. A., Ertelt, J. M., Weigele, B., Selyunin, A. S., ... Alto, N. M. (2013). Proteolytic elimination of N-myristoyl modifications by the Shigella virulence factor IpaJ. Nature, 496(7443), 106-109. https://doi.org/10.1038/nature12004

Proteolytic elimination of N-myristoyl modifications by the Shigella virulence factor IpaJ. / Burnaevskiy, Nikolay; Fox, Thomas G.; Plymire, Daniel A.; Ertelt, James M.; Weigele, Bethany; Selyunin, Andrey S.; Way, Sing Sing; Patrie, Steven M.; Alto, Neal M.

In: Nature, Vol. 496, No. 7443, 04.04.2013, p. 106-109.

Research output: Contribution to journalArticle

Burnaevskiy, N, Fox, TG, Plymire, DA, Ertelt, JM, Weigele, B, Selyunin, AS, Way, SS, Patrie, SM & Alto, NM 2013, 'Proteolytic elimination of N-myristoyl modifications by the Shigella virulence factor IpaJ', Nature, vol. 496, no. 7443, pp. 106-109. https://doi.org/10.1038/nature12004
Burnaevskiy N, Fox TG, Plymire DA, Ertelt JM, Weigele B, Selyunin AS et al. Proteolytic elimination of N-myristoyl modifications by the Shigella virulence factor IpaJ. Nature. 2013 Apr 4;496(7443):106-109. https://doi.org/10.1038/nature12004
Burnaevskiy, Nikolay ; Fox, Thomas G. ; Plymire, Daniel A. ; Ertelt, James M. ; Weigele, Bethany ; Selyunin, Andrey S. ; Way, Sing Sing ; Patrie, Steven M. ; Alto, Neal M. / Proteolytic elimination of N-myristoyl modifications by the Shigella virulence factor IpaJ. In: Nature. 2013 ; Vol. 496, No. 7443. pp. 106-109.
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