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
Kirby N SwatekDavid Komander

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.

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Aug 22, 2018·Bioscience Reports·Anja BastersGünter Fritz
Nov 9, 2018·Journal of Virology·Linda J VisserFrank J M van Kuppeveld
Aug 16, 2019·Nature·Kirby N SwatekDavid Komander
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Jun 3, 2021·Viruses·Azman Embarc-BuhEncarnacion Martinez-Salas

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Methods Mentioned

BETA
transfection
Infection
ELISAs
Protein Purification

Software Mentioned

pro
Lb

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