Calicivirus 3C-like proteinase inhibits cellular translation by cleavage of poly(A)-binding protein

Muge Kuyumcu-Martinez, Gaël Belliot, Stanislav V. Sosnovtsev, Kyeong Ok Chang, Kim Y. Green, Richard E. Lloyd

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

Caliciviruses are single-stranded RNA viruses that cause a wide range of diseases in both humans and animals, but little is known about the regulation of cellular translation during infection. We used two distinct calicivirus strains, MD145-12 (genus Norovirus) and feline calicivirus (FCV) (genus Vesivirus), to investigate potential strategies used by the caliciviruses to inhibit cellular translation. Recombinant 3C-like proteinases (r3CL pro) from norovirus and FCV were found to cleave poly(A)-binding protein (PABP) in the absence of other viral proteins. The norovirus r3CL pro PABP cleavage products were indistinguishable from those generated by poliovirus (PV) 3Cpro cleavage, while the FCV r3CL pro products differed due to cleavage at an alternate cleavage site 24 amino acids downstream of one of the PV 3Cpro cleavage sites. All cleavages by calicivirus or PV proteases separated the C-terminal domain of PABP that binds translation factors eIF4B and eRF3 from the N-terminal RNA-binding domain of PABP. The effect of PABP cleavage by the norovirus r3CLpro was analyzed in HeLa cell translation extracts, and the presence of r3CL pro inhibited translation of both endogenous and exogenous mRNAs. Translation inhibition was poly(A) dependent, and replenishment of the extracts with PABP restored translation. Analysis of FCV-infected feline kidney cells showed that the levels of de novo cellular protein synthesis decreased over time as virus-specific proteins accumulated, and cleavage of PABP occurred in virus-infected cells. Our data indicate that the calicivirus 3CLpro, like PV 3Cpro, mediates the cleavage of PABP as part of its strategy to inhibit cellular translation. PABP cleavage may be a common mechanism among certain virus families to manipulate cellular translation.

Original languageEnglish (US)
Pages (from-to)8172-8182
Number of pages11
JournalJournal of virology
Volume78
Issue number15
DOIs
StatePublished - Aug 1 2004
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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