Abstract
Herpesviruses acquire their membrane envelopes in the cytoplasm of infected cells via a molecular mechanism that remains unclear. Herpes simplex virus (HSV)-1 proteins pUL7 and pUL51 form a complex required for efficient virus envelopment. We show that interaction between homologues of pUL7 and pUL51 is conserved across human herpesviruses, as is their association with trans-Golgi membranes. We characterized the HSV-1 pUL7:pUL51 complex by solution scattering and chemical crosslinking, revealing a 1:2 complex that can form higher-order oligomers in solution, and we solved the crystal structure of the core pUL7:pUL51 heterodimer. While pUL7 adopts a previously-unseen compact fold, the helix-turn-helix conformation of pUL51 resembles the cellular endosomal complex required for transport (ESCRT)-III component CHMP4B and pUL51 forms ESCRT-III-like filaments, suggesting a direct role for pUL51 in promoting membrane scission during virus assembly. Our results provide a structural framework for understanding the role of the conserved pUL7:pUL51 complex in herpesvirus assembly.
Highlights
Herpesviruses are highly prevalent human and animal pathogens that cause life-long infections and result in diseases ranging from cold sores and genital lesions to viral encephalitis (HSV-1), congenital birth defects and cancer (e.g. Kaposi’s sarcoma associated herpesvirus, KSHV) (Evans et al, 2013; Virgin et al, 2009)
Herpes simplex virus (HSV)-1 tegument proteins pUL7 and pUL51 promote virus assembly by stimulating the cytoplasmic wrapping of nascent virions (Albecka et al, 2017; Roller and Fetters, 2015). pUL7 and pUL51 form a complex that co-localizes with Golgi markers both during infection and when co-transfected into cells (Albecka et al, 2017; Roller and Fetters, 2015; Nozawa et al, 2003), palmitoylation of residue Cys9 being required for pUL51 membrane association (Nozawa et al, 2003)
Multi-angle light scattering (MALS) analysis showed the complex to elute from size-exclusion chromatography (SEC) as two peaks with molecular masses of 79.0 ± 1.8 kDa and 165.5 ± 1.1 kDa (Figure 1A), consistent with pUL7 and pUL51 forming a 1:2 heterotrimer in solution that dimerizes at higher concentrations to form a 2:4 heterohexamer
Summary
Herpesviruses are highly prevalent human and animal pathogens that cause life-long infections and result in diseases ranging from cold sores and genital lesions (herpes simplex virus, HSV) to viral encephalitis (HSV-1), congenital birth defects (human cytomegalovirus, HCMV) and cancer (e.g. Kaposi’s sarcoma associated herpesvirus, KSHV) (Evans et al, 2013; Virgin et al, 2009). Microbiology and Infectious Disease Structural Biology and Molecular Biophysics eLife digest Most people suffer from occasional cold sores, which are caused by the herpes simplex virus This virus causes infections that last your entire life, but for the most part it lies dormant in your cells and reactivates only at times of stress. Further experiments showed that the equivalents of pUL7 and pUL51 in other members of the herpes virus family bind to each other in a similar way These findings reveal that herpes simplex viruses and their close relatives have evolved a different strategy than many other viruses to steal membranes from host cells. PUL51 homologues from varicella-zoster virus (VZV), co-localize with trans-Golgi markers in infected cells (Selariu et al, 2012; Wang et al, 2017) and deletion of pORF7 causes a defect in cytoplasmic envelopment (Jiang et al, 2017). We show that formation of the pUL7:pUL51 complex and its association with the trans-Golgi network is conserved across a-, b- and g-herpesviruses, consistent with a conserved function for this complex in herpesvirus assembly
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