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  • Title: UL25 Capsid Binding Facilitates Mechanical Maturation of the Herpesvirus Capsid and Allows Retention of Pressurized DNA.
    Author: Freeman KG, Huffman JB, Homa FL, Evilevitch A.
    Journal: J Virol; 2021 Sep 27; 95(20):e0075521. PubMed ID: 34346766.
    Abstract:
    The maturation process that occurs in most viruses is evolutionarily driven, as it resolves several conflicting virion assembly requirements. During herpesvirus assembly in a host cell nucleus, micron-long double-stranded herpes DNA is packaged into a nanometer-sized procapsid. This leads to strong confinement of the viral genome, resulting in tens of atmospheres of intracapsid DNA pressure. Yet, the procapsid is unstable due to weak reversible interactions between its protein subunits, which ensures free energy minimization and reduces assembly errors. In this work, we show that herpesviruses resolve these contradictory capsid requirements through a mechanical capsid maturation process facilitated by multifunctional auxiliary protein UL25. Through mechanical interrogation of herpes simplex virus 1 (HSV-1) capsid with atomic force microscopy nano-indentation, we show that UL25 binding at capsid vertices post-assembly provides the critical capsid reinforcement required for stable DNA encapsidation; the absence of UL25 binding leads to capsid rupture. Furthermore, we demonstrate that gradual capsid reinforcement is a feasible maturation mechanism facilitated by progressive UL25 capsid binding, which is likely correlated with DNA packaging progression. This work provides insight into elegantly programmed viral assembly machinery, where targeting of capsid assembly mechanics presents a new antiviral strategy that is resilient to the development of drug resistance. IMPORTANCE Most viruses undergo a maturation process from a weakly assembled particle to a stable virion. Herpesvirus capsid undergoes mechanical maturation to withstand tens of atmospheres of DNA pressure. We demonstrate that this mechanical capsid maturation is mainly facilitated through binding of auxiliary protein UL25 in herpes simplex virus 1 (HSV-1) capsid vertices. We show that UL25 binding provides the critical capsid reinforcement required for stable DNA encapsidation. Our data also suggest that gradual capsid reinforcement by progressive UL25 binding is a feasible capsid maturation mechanism, correlated with DNA packaging progression.
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