The herpesvirus capsid assembles in the nucleus as an immature procapsid precursor built around viral scaffold proteins. The event that initiates procapsid maturation is unknown, but it is dependent upon activation of the VP24 internal protease. Scaffold cleavage triggers angularization of the shell and its decoration with the VP26 and pUL25 capsid-surface proteins. In both the procapsid and mature angularized capsid, the apical region of the major capsid protein (VP5) is surface exposed. We investigated whether the VP5 apical region contributes to intracellular transport dynamics following entry into primary sensory neurons and also tested the hypothesis that conserved negatively charged amino acids in the apical region contribute to VP26 acquisition. To our surprise, neither hypothesis proved true. Instead, mutation of glutamic acid residues in the apical region delayed viral propagation and induced focal capsid accumulations in nuclei. Examination of capsid morphogenesis based on epitope unmasking, capsid composition, and ultrastructural analysis indicated that these clusters consisted of procapsids. The results demonstrate that, in addition to established events that occur inside the capsid, the exterior capsid shell promotes capsid morphogenesis and maturation. Herpesviruses assemble capsids and encapsidate their genomes by a process that is unlike those of other mammalian viruses but is similar to those of some bacteriophage. Many important aspects of herpesvirus morphogenesis remain enigmatic, including how the capsid shell matures into a stable angularized configuration. Capsid maturation is triggered by activation of a protease that cleaves an internal protein scaffold. We report on the fortuitous discovery that a region of the major capsid protein that is exposed on the outer surface of the capsid also contributes to capsid maturation, demonstrating that the morphogenesis of the capsid shell from its procapsid precursor to the mature angularized form is dependent upon internal and external components of the megastructure.
40The herpesvirus capsid assembles in the nucleus as an immature procapsid 41 precursor built around viral scaffold proteins. The event that initiates procapsid 42 maturation is unknown, but it is dependent upon activation of the VP24 internal 43 protease. Scaffold cleavage triggers angularization of the shell and its decoration 44 with the VP26 and pUL25 capsid-surface proteins. In both the procapsid and 45 mature angularized capsid, the apical region of the major capsid protein (VP5) is 46 surface exposed. We investigated whether the VP5 apical region contributes to 47 intracellular transport dynamics following entry into primary sensory neurons and 48 also tested the hypothesis that conserved negatively-charged amino acids in the 49 apical region contribute to VP26 acquisition. To our surprise neither hypothesis 50 proved true. Instead, mutation of glutamic acid residues in the apical region 51 delayed viral propagation and induced focal capsid accumulations in nuclei. 52Examination of capsid morphogenesis based on epitope unmasking, capsid 53 composition, and ultrastructural analysis indicated that these clusters consisted 54 of procapsids. The results demonstrate that, in addition to established events that 55 occur inside the capsid, the exterior capsid shell promotes capsid morphogenesis 56 and maturation. 57 58 IMPORTANCE 59Herpesviruses assemble capsids and encapsidate their genomes by a process 60 that is unlike other mammalian viruses but is similar to some bacteriophage. 61 Many important aspects of herpesvirus morphogenesis remain enigmatic, 62including how the capsid shell matures into a stable angularized configuration. 63Capsid maturation is triggered by activation of a protease that cleaves an internal 64 protein scaffold. We report on the fortuitous discovery that a region of the major 65 capsid protein that is exposed on the outer surface of the capsid also contributes 66 to capsid maturation, demonstrating that the morphogenesis of the capsid shell 67 from its procapsid precursor to the mature angularized form is dependent upon 68 internal and external components of the megastructure. 69
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