Abstract
Progeny capsids of herpesviruses leave the nucleus by budding through the nuclear envelope. Two viral proteins, the membrane protein pUL34 and the nucleo-phosphoprotein pUL31 form the nuclear egress complex that is required for capsid egress out of the nucleus. All pUL31 orthologs are composed of a diverse N-terminal domain with 1 to 3 basic patches and a conserved C-terminal domain. To decipher the functions of the N-terminal domain, we have generated several Herpes simplex virus mutants and show here that the N-terminal domain of pUL31 is essential with basic patches being critical for viral propagation. pUL31 and pUL34 entered the nucleus independently of each other via separate routes and the N-terminal domain of pUL31 was required to prevent their premature interaction in the cytoplasm. Unexpectedly, a classical bipartite nuclear localization signal embedded in this domain was not required for nuclear import of pUL31. In the nucleus, pUL31 associated with the nuclear envelope and newly formed capsids. Viral mutants lacking the N-terminal domain or with its basic patches neutralized still associated with nucleocapsids but were unable to translocate them to the nuclear envelope. Replacing the authentic basic patches with a novel artificial one resulted in HSV1(17+)Lox-UL31-hbpmp1mp2, that was viable but delayed in nuclear egress and compromised in viral production. Thus, while the C-terminal domain of pUL31 is sufficient for the interaction with nucleocapsids, the N-terminal domain was essential for capsid translocation to sites of nuclear egress and a coordinated interaction with pUL34. Our data indicate an orchestrated sequence of events with pUL31 binding to nucleocapsids and escorting them to the inner nuclear envelope. We propose a common mechanism for herpesviral nuclear egress: pUL31 is required for intranuclear translocation of nucleocapsids and subsequent interaction with pUL34 thereby coupling capsid maturation with primary envelopment.
Highlights
Morphogenesis of herpesviral capsids is an intricate process initiated in the infected nucleus [1]
Instead herpesviruses apply an evolutionarily conserved mechanism for nuclear export of capsids called nuclear egress. This process is initiated by docking of capsids at the inner nuclear membrane, budding of enveloped capsids into the perinuclear space followed by de-envelopment and release of capsids to the cytoplasm where further maturation occurs
Two viral proteins conserved throughout the herpesvirus family, the membrane protein pUL34 and the phosphoprotein pUL31 form the nuclear egress complex that is critical for primary envelopment
Summary
Morphogenesis of herpesviral capsids is an intricate process initiated in the infected nucleus [1]. A fragile procapsid is formed and packaged with one copy of the viral genome that is generated by cleavage of replicated concatameric DNA molecules. During this process, the rather spherical procapsids change their conformation and mature into the icosahedral and more stable C capsids. The rather spherical procapsids change their conformation and mature into the icosahedral and more stable C capsids These accumulate in large numbers in capsid assembly sites and in the nucleoplasm. How mature capsids are released from sites of assembly, and how they translocate from there to the nuclear envelope is not completely understood, and their mode of transport to the nuclear periphery is discussed controversially [5,6,7,8,9]
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