Irreversible inactivation of ISG15 by a viral leader protease enables alternative infection detection strategies

Kirby N. Swatek, Martina Aumayr, Jonathan Pruneda, Linda J. Visser, Stephen Berryman, Anja F. Kueck, Paul P. Geurink, Huib Ovaa, Frank J.M. van Kuppeveld, Tobias J. Tuthill, Tim Skern, David Komander

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

In response to viral infection, cells mount a potent inflammatory response that relies on ISG15 and ubiquitin posttranslational modifications. Many viruses use deubiquitinases and deISGylases that reverse these modifications and antagonize host signaling processes. We here reveal that the leader protease, Lbpro, from foot-and-mouth disease virus (FMDV) targets ISG15 and to a lesser extent, ubiquitin in an unprecedented manner. Unlike canonical deISGylases that hydrolyze the isopeptide linkage after the C-terminal GlyGly motif, Lbpro cleaves the peptide bond preceding the GlyGly motif. Consequently, the GlyGly dipeptide remains attached to the substrate Lys, and cleaved ISG15 is rendered incompetent for reconjugation. A crystal structure of Lbpro bound to an engineered ISG15 suicide probe revealed the molecular basis for ISG15 proteolysis. Importantly, anti-GlyGly antibodies, developed for ubiquitin proteomics, are able to detect Lbpro cleavage products during viral infection. This opens avenues for infection detection of FMDV based on an immutable, host-derived epitope.

Original languageEnglish (US)
Pages (from-to)2371-2376
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number10
DOIs
StatePublished - Mar 6 2018
Externally publishedYes

Fingerprint

Ubiquitin
Foot-and-Mouth Disease Virus
Peptide Hydrolases
Virus Diseases
Infection
Molecular Probes
Dipeptides
Post Translational Protein Processing
Proteomics
Suicide
Proteolysis
Epitopes
Anti-Idiotypic Antibodies
Viruses
Peptides

Keywords

  • FMDV
  • ISG15
  • Structure
  • Ubiquitin
  • Viral signaling

ASJC Scopus subject areas

  • General

Cite this

Irreversible inactivation of ISG15 by a viral leader protease enables alternative infection detection strategies. / Swatek, Kirby N.; Aumayr, Martina; Pruneda, Jonathan; Visser, Linda J.; Berryman, Stephen; Kueck, Anja F.; Geurink, Paul P.; Ovaa, Huib; van Kuppeveld, Frank J.M.; Tuthill, Tobias J.; Skern, Tim; Komander, David.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 10, 06.03.2018, p. 2371-2376.

Research output: Contribution to journalArticle

Swatek, KN, Aumayr, M, Pruneda, J, Visser, LJ, Berryman, S, Kueck, AF, Geurink, PP, Ovaa, H, van Kuppeveld, FJM, Tuthill, TJ, Skern, T & Komander, D 2018, 'Irreversible inactivation of ISG15 by a viral leader protease enables alternative infection detection strategies', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 10, pp. 2371-2376. https://doi.org/10.1073/pnas.1710617115
Swatek, Kirby N. ; Aumayr, Martina ; Pruneda, Jonathan ; Visser, Linda J. ; Berryman, Stephen ; Kueck, Anja F. ; Geurink, Paul P. ; Ovaa, Huib ; van Kuppeveld, Frank J.M. ; Tuthill, Tobias J. ; Skern, Tim ; Komander, David. / Irreversible inactivation of ISG15 by a viral leader protease enables alternative infection detection strategies. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 10. pp. 2371-2376.
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