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PMID: 11836384 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

Journal of virology ·Vol. 76 ·No. 5 ·2002-03-00 ·Pages 2062-74

Kuyumcu-Martinez NM, Joachims M, Lloyd RE

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 (2A(pro)) or 3C protease (3C(pro)). 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, 3C(pro) is more efficient in cleaving PABP in ribosome-enriched fractions than 2A(pro) in vitro. In addition, binding of PABP to poly(A) RNA stimulates 3C(pro)-mediated cleavage and inhibits 2A(pro)-mediated cleavage. These results suggest that 3C(pro) 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.

MeSH Terms
3C Viral Proteases Amino Acid Sequence Cysteine Endopeptidases/metabolism HeLa Cells Humans Molecular Sequence Data Poliovirus/enzymology Poly(A)-Binding Proteins RNA-Binding Proteins/chemistry,metabolism Ribosomes/metabolism Subcellular Fractions Viral Proteins/metabolism
Chemicals
Poly(A)-Binding Proteins RNA-Binding Proteins Viral Proteins Cysteine Endopeptidases 3C Viral Proteases 3C proteases picornain 2A, Picornavirus
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Kuyumcu-Martinez N Muge
Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Joachims Michelle
Lloyd Richard E
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/jvi.76.5.2062-2074.2002
Published
2002-03-00
Pages
2062-74
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC135927
Subset
IM
Grants
NIGMS NIH HHS · R01 GM059803 · United States
NIAID NIH HHS · AI 27914 · United States
NIGMS NIH HHS · GM 58903 · United States
External Links
PubMed source DOI: 10.1128/jvi.76.5.2062-2074.2002 PMC Full Text View journal details
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