Flavivirus Premembrane Protein Cleavage and Spike Heterodimer Secretion Require the Function of the Viral Proteinase NS3

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1993 Jul 1

PMID 8392191

Citations 68

Authors

M Lobigs

Affiliations

Soon will be listed here.

Abstract

Flavivirus protein biosynthesis involves the proteolytic processing of a single polyprotein precursor by host- and virus-encoded proteinases. In this study, the requirement for the proteolytic function of the viral proteinase NS3 for correct processing of a polyprotein segment encompassing the Murray Valley encephalitis virus structural proteins is shown. The NS3-mediated cleavage in the structural polyprotein region presumably releases the capsid protein from its membrane anchor and triggers the appearance of the premembrane (prM) protein. This suggests that cleavage of prM by signal peptidase in the lumen of the endoplasmic reticulum is under control of a cytoplasmic cleavage catalyzed by a viral proteinase. The function of the viral proteinase is also essential for secretion of flaviviral spike proteins when expressed from cDNA via vaccinia virus recombinants or in COS cell transfections. This has important implications for the design of flavivirus subunit vaccines.

Citing Articles

Development of a novel virus-like particle-based vaccine for preventing tick-borne encephalitis virus infection.

Tang J, Fu M, Xu C, Xue B, Zhou A, Chen S Virol Sin. 2023; 38(5):767-777.

PMID: 37328107 PMC: 10590693. DOI: 10.1016/j.virs.2023.06.003.

An optimized messenger RNA vaccine candidate protects non-human primates from Zika virus infection.

Bollman B, Nunna N, Bahl K, Hsiao C, Bennett H, Butler S NPJ Vaccines. 2023; 8(1):58.

PMID: 37080988 PMC: 10119314. DOI: 10.1038/s41541-023-00656-4.

SPCS1-Dependent E2-p7 processing determines HCV Assembly efficiency.

Alzahrani N, Wu M, Sousa C, Kalinina O, Welsch C, Yi M PLoS Pathog. 2022; 18(2):e1010310.

PMID: 35130329 PMC: 8853643. DOI: 10.1371/journal.ppat.1010310.

Potential Role of Flavivirus NS2B-NS3 Proteases in Viral Pathogenesis and Anti-flavivirus Drug Discovery Employing Animal Cells and Models: A Review.

Wahaab A, Mustafa B, Hameed M, Stevenson N, Anwar M, Liu K Viruses. 2022; 14(1).

PMID: 35062249 PMC: 8781031. DOI: 10.3390/v14010044.

The E Carboxyterminus: Much More Than a Membrane Anchor.

Tews B, Klingebeil A, Kuhn J, Franzke K, Rumenapf T, Meyers G Viruses. 2021; 13(7).

PMID: 34201636 PMC: 8310223. DOI: 10.3390/v13071203.

References

BRANDT W . From the World Health Organization. Current approaches to the development of dengue vaccines and related aspects of the molecular biology of flaviviruses. J Infect Dis. 1988; 157(5):1105-11. DOI: 10.1093/infdis/157.5.1105. View

Coia G, Parker M, Speight G, Byrne M, WESTAWAY E . Nucleotide and complete amino acid sequences of Kunjin virus: definitive gene order and characteristics of the virus-specified proteins. J Gen Virol. 1988; 69 ( Pt 1):1-21. DOI: 10.1099/0022-1317-69-1-1. View

Zhang Y, Hayes E, McCarty T, Dubois D, Summers P, Eckels K . Immunization of mice with dengue structural proteins and nonstructural protein NS1 expressed by baculovirus recombinant induces resistance to dengue virus encephalitis. J Virol. 1988; 62(8):3027-31. PMC: 253742. DOI: 10.1128/JVI.62.8.3027-3031.1988. View

Krausslich H, Wimmer E . Viral proteinases. Annu Rev Biochem. 1988; 57:701-54. DOI: 10.1146/annurev.bi.57.070188.003413. View

Nowak T, Farber P, WENGLER G . Analyses of the terminal sequences of West Nile virus structural proteins and of the in vitro translation of these proteins allow the proposal of a complete scheme of the proteolytic cleavages involved in their synthesis. Virology. 1989; 169(2):365-76. DOI: 10.1016/0042-6822(89)90162-1. View

Bray M, Zhao B, Markoff L, Eckels K, Chanock R, Lai C . Mice immunized with recombinant vaccinia virus expressing dengue 4 virus structural proteins with or without nonstructural protein NS1 are protected against fatal dengue virus encephalitis. J Virol. 1989; 63(6):2853-6. PMC: 250798. DOI: 10.1128/JVI.63.6.2853-2856.1989. View

Markoff L . In vitro processing of dengue virus structural proteins: cleavage of the pre-membrane protein. J Virol. 1989; 63(8):3345-52. PMC: 250908. DOI: 10.1128/JVI.63.8.3345-3352.1989. View

Speight G, WESTAWAY E . Carboxy-terminal analysis of nine proteins specified by the flavivirus Kunjin: evidence that only the intracellular core protein is truncated. J Gen Virol. 1989; 70 ( Pt 8):2209-14. DOI: 10.1099/0022-1317-70-8-2209. View

Ruiz-Linares A, Cahour A, Despres P, Girard M, Bouloy M . Processing of yellow fever virus polyprotein: role of cellular proteases in maturation of the structural proteins. J Virol. 1989; 63(10):4199-209. PMC: 251034. DOI: 10.1128/JVI.63.10.4199-4209.1989. View

10.

Matsuura Y, Miyamoto M, Sato T, Morita C, Yasui K . Characterization of Japanese encephalitis virus envelope protein expressed by recombinant baculoviruses. Virology. 1989; 173(2):674-82. DOI: 10.1016/0042-6822(89)90580-1. View

11.

Rapoport T . Transport of proteins across the endoplasmic reticulum membrane. Science. 1992; 258(5084):931-6. DOI: 10.1126/science.1332192. View

12.

Dalbey R, von Heijne G . Signal peptidases in prokaryotes and eukaryotes--a new protease family. Trends Biochem Sci. 1992; 17(11):474-8. DOI: 10.1016/0968-0004(92)90492-r. View

13.

Hellen C, Krausslich H, Wimmer E . Proteolytic processing of polyproteins in the replication of RNA viruses. Biochemistry. 1989; 28(26):9881-90. DOI: 10.1021/bi00452a001. View

14.

Lobigs M, Garoff H . Fusion function of the Semliki Forest virus spike is activated by proteolytic cleavage of the envelope glycoprotein precursor p62. J Virol. 1990; 64(3):1233-40. PMC: 249238. DOI: 10.1128/JVI.64.3.1233-1240.1990. View

15.

Randolph V, Winkler G, Stollar V . Acidotropic amines inhibit proteolytic processing of flavivirus prM protein. Virology. 1990; 174(2):450-8. DOI: 10.1016/0042-6822(90)90099-d. View

16.

Yasuda A, Ogimoto M, Miyamoto M, Sata T, Sato T, Takamura C . Induction of protective immunity in animals vaccinated with recombinant vaccinia viruses that express PreM and E glycoproteins of Japanese encephalitis virus. J Virol. 1990; 64(6):2788-95. PMC: 249459. DOI: 10.1128/JVI.64.6.2788-2795.1990. View

17.

Chambers T, McCourt D, Rice C . Production of yellow fever virus proteins in infected cells: identification of discrete polyprotein species and analysis of cleavage kinetics using region-specific polyclonal antisera. Virology. 1990; 177(1):159-74. DOI: 10.1016/0042-6822(90)90470-c. View

18.

Lobigs M, Zhao H, Garoff H . Function of Semliki Forest virus E3 peptide in virus assembly: replacement of E3 with an artificial signal peptide abolishes spike heterodimerization and surface expression of E1. J Virol. 1990; 64(9):4346-55. PMC: 247902. DOI: 10.1128/JVI.64.9.4346-4355.1990. View

19.

Preugschat F, Yao C, Strauss J . In vitro processing of dengue virus type 2 nonstructural proteins NS2A, NS2B, and NS3. J Virol. 1990; 64(9):4364-74. PMC: 247904. DOI: 10.1128/JVI.64.9.4364-4374.1990. View

20.

Chambers T, Weir R, Grakoui A, McCourt D, Bazan J, Fletterick R . Evidence that the N-terminal domain of nonstructural protein NS3 from yellow fever virus is a serine protease responsible for site-specific cleavages in the viral polyprotein. Proc Natl Acad Sci U S A. 1990; 87(22):8898-902. PMC: 55067. DOI: 10.1073/pnas.87.22.8898. View