This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ito, K.
Right arrow Articles by Tong, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ito, K.
Right arrow Articles by Tong, S.

 Previous Article  |  Next Article 

Journal of Virology, April 2009, p. 3507-3517, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02348-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Characterization of Genotype-Specific Carboxyl-Terminal Cleavage Sites of Hepatitis B Virus e Antigen Precursor and Identification of Furin as the Candidate Enzyme{triangledown}

Kiyoaki Ito,1 Kyun-Hwan Kim,1,2 Anna Suk-Fong Lok,3 and Shuping Tong1*

The Liver Research Center, Rhode Island Hospital and Warren Alpert School of Medicine, Brown University, Providence, Rhode Island,1 Department of Pharmacology, School of Medicine, and Center for Diagnostic Medicine, Konkuk University, Seoul, Korea,2 Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, Michigan3

Received 11 November 2008/ Accepted 25 January 2009

Hepatitis B e antigen (HBeAg) is a secreted version of hepatitis B virus (HBV) core protein that promotes immune tolerance and persistent infection. It is derived from a translation product of the precore/core gene by two proteolytic cleavage events: removal of the amino-terminal signal peptide and removal of the carboxyl-terminal arginine-rich sequence. Four RXXR motifs are present at the carboxyl terminus of the HBeAg precursor, with the first two fused as 151RRGRSPR157. Genotype A possesses two extra amino acids at the first motif (151RRDRGRSPR159), which weakens the first motif and separates it from the second one. Western blot analysis of patient sera revealed a single HBeAg form for genotypes B to D but two additional forms of larger sizes for genotype A. Site-directed mutagenesis and transfection experiments with human hepatoma cell lines indicated that HBeAg of genotype B is derived from cleavage at the first (151RRGR154) motif. The major HBeAg form of genotype A corresponds to cleavage at the second (156RSPR159) motif, and the other two forms are cleavage products of the first (151RRDR154) and third (166RRRR169) motifs, respectively. Only the cleavage product of the third motif of genotype A was observed in furin-deficient LoVo cells, and an inhibitor of furin-like proprotein convertases blocked cleavage of the first and second motifs in human hepatoma cells. In conclusion, our study reveals genotypic differences in HBeAg processing and implicates furin as the major enzyme involved in the cleavage of the first and second RXXR motifs.

* Corresponding author. Mailing address: Liver Research Center, 55 Claverick Street, Providence, RI 02906. Phone: (401) 444-7365. Fax: (401) 444-2939. E-mail: Shuping_Tong_MD{at}Brown.edu

{triangledown} Published ahead of print on 4 February 2009.

Journal of Virology, April 2009, p. 3507-3517, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02348-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Yamada, Y., Liu, D. X. (2009). Proteolytic Activation of the Spike Protein at a Novel RRRR/S Motif Is Implicated in Furin-Dependent Entry, Syncytium Formation, and Infectivity of Coronavirus Infectious Bronchitis Virus in Cultured Cells. J. Virol. 83: 8744-8758 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»