Efficient cleavage of ribosome-associated poly(A)-binding protein by enterovirus 3C protease

Neslihan Martinez, Michelle Joachims, Richard E. Lloyd

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Poliovirus (PV) causes a rapid and drastic inhibition of host cell cap-dependent protein synthesis during infection while preferentially allowing cap-independent translation of its own genomic RNA via an internal ribosome entry site element. Inhibition of cap-dependent translation is partly mediated by cleavage of an essential translation initiation factor, eIF4GI, during PV infection. In addition to cleavage of eIF4GI, cleavage of eIF4GII and poly(A)-binding protein (PABP) has been recently proposed to contribute to complete host translation shutoff; however, the relative importance of eIF4GII and PABP cleavage has not been determined. At times when cap-dependent translation is first blocked during infection, only 25 to 35% of the total cellular PABP is cleaved; therefore, we hypothesized that the pool of PABP associated with polysomes may be preferentially targeted by viral proteases. We have investigated what cleavage products of PABP are produced in vivo and the substrate determinants for cleavage of PABP by 2A protease (2Apro) or 3C protease (3Cpro). Our results show that PABP in ribosome-enriched fractions is preferentially cleaved in vitro and in vivo compared to PABP in other fractions. Furthermore, we have identified four N-terminal PABP cleavage products produced during PV infection and have shown that viral 3C protease generates three of the four cleavage products. Also, 3Cpro is more efficient in cleaving PABP in ribosome-enriched fractions than 2Apro in vitro. In addition, binding of PABP to poly(A) RNA stimulates 3Cpro-mediated cleavage and inhibits 2Apro-mediated cleavage. These results suggest that 3Cpro plays a major role in processing PABP during virus infection and that the interaction of PABP with translation initiation factors, ribosomes, or poly(A) RNA may promote its cleavage by viral 2A and 3C proteases.

Original languageEnglish (US)
Pages (from-to)2062-2074
Number of pages13
JournalJournal of Virology
Volume76
Issue number5
DOIs
StatePublished - 2002
Externally publishedYes

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Poly(A)-Binding Proteins
Enterovirus
ribosomes
Ribosomes
binding proteins
proteinases
translation (genetics)
Enterovirus C
Poliovirus
Peptide Hydrolases
Peptide Initiation Factors
infection
messenger RNA
Infection
3C proteases
Translational Peptide Chain Initiation
Messenger RNA
polyribosomes
Polyribosomes
Virus Diseases

ASJC Scopus subject areas

  • Immunology

Cite this

Efficient cleavage of ribosome-associated poly(A)-binding protein by enterovirus 3C protease. / Martinez, Neslihan; Joachims, Michelle; Lloyd, Richard E.

In: Journal of Virology, Vol. 76, No. 5, 2002, p. 2062-2074.

Research output: Contribution to journalArticle

Martinez, Neslihan ; Joachims, Michelle ; Lloyd, Richard E. / Efficient cleavage of ribosome-associated poly(A)-binding protein by enterovirus 3C protease. In: Journal of Virology. 2002 ; Vol. 76, No. 5. pp. 2062-2074.
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