A single amino acid substitution in the capsid of foot-and-mouth disease virus can increase acid lability and confer resistance to acid-dependent uncoating inhibition.
The acid-dependent disassembly of foot-and-mouth disease virus (FMDV) is required for viral RNA release from endosomes to initiate replication. Although the FMDV capsid disassembles at acid pH, mutants escaping inhibition by NH(4)Cl of endosomal acidification were found to constitute about 10% of the viruses recovered from BHK-21 cells infected with FMDV C-S8c1. For three of these mutants, the degree of NH(4)Cl resistance correlated with the sensitivity of the virion to acid-induced inactivation of its infectivity. Capsid sequencing revealed the presence in each of these mutants of a different amino acid substitution (VP3 A123T, VP3 A118V, and VP2 D106G) that affected a highly conserved residue among FMDVs located close to the capsid interpentameric interfaces. These residues may be involved in the modulation of the acid-induced dissociation of the FMDV capsid. The substitution VP3 A118V present in mutant c2 was sufficient to confer full resistance to NH(4)Cl and concanamycin A (a V-ATPase inhibitor that blocks endosomal acidification) as well as to increase the acid sensitivity of the virion to an extent similar to that exhibited by mutant c2 relative to the sensitivity of the parental virus C-S8c1. In addition, the increased propensity to dissociation into pentameric subunits of virions bearing substitution VP3 A118V indicates that this replacement also facilitates the dissociation of the FMDV capsid.
Martín-Acebes
Miguel A
MA
Centro de Biología Molecular Severo Ochoa, Cantoblanco 28049, Madrid, Spain.
Rincón
Verónica
V
Armas-Portela
Rosario
R
Mateu
Mauricio G
MG
Sobrino
Francisco
F
D000143:Acids / Q000737:chemistry*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000643:Ammonium Chloride / Q000378:metabolism; D000818:Animals; D002213:Capsid / Q000737:chemistry / Q000502:physiology*; D002417:Cattle; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism; D005536:Foot-and-Mouth Disease / Q000378:metabolism / Q000821:virology; D029544:Foot-and-Mouth Disease Virus / Q000235:genetics / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011487:Protein Conformation; D014771:Virion / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D014779:Virus Replication / Q000235:genetics
D000143:Acids; D016023:Integrins; D000643:Ammonium Chloride