Getting to and through the inner nuclear membrane during herpesvirus nuclear egress

Abstract

Herpesviruses, like most DNA viruses, replicate and package their genomes into capsids in the host cell nucleus. Capsids then transit to the cytoplasm in a fascinating process called nuclear egress, which includes several unusual steps: Movement of capsids from the nuclear interior to the periphery, disruption of the nuclear lamina, capsid budding through the inner nuclear membrane, and fusion of enveloped particles with the outer nuclear membrane. Here, we review recent advances and emerging questions relating to herpesvirus nuclear egress, emphasizing controversies regarding mechanisms for capsid trafficking to the nuclear periphery, and implications of recent structures of the two-subunit, viral nuclear egress complex for the process, particularly at the step of budding through the inner nuclear membrane.

The human cytomegalovirus nuclear egress complex unites multiple functions: Recruitment of effectors, nuclear envelope rearrangement, and docking to nuclear capsids

“…As a characteristic feature of herpesviruses, genomic replication starts in the host cell nucleus, where preformed capsids are packaged and exported to the cytoplasm for further virion maturation. The transition of capsids through the NE is a multistep regulatory process, termed nuclear egress . During this process, the NE is reorganized at specific sites with a profound importance of phosphorylation‐triggered distortion of the nuclear lamina .…”

“…For this reason, it will be highly challenging to define those structural target points that allow for the positioning of NEC‐based pan‐herpesviral inhibitory small molecules. It is obvious that steric inhibitors of NEC subunit assembly, either blocking the interaction of core NEC or multimeric NEC‐associated factors, may have great potential for pharmacological development . Moreover, alternative mechanisms of NEC inhibition could be similarly effective, eg, the inhibitory targeting of NEC phosphorylation.…”

“…The transition of capsids through the NE is a multistep regulatory process, termed nuclear egress. [97][98][99][100][101][102][103][104][105][106][107][108][109] During this process, the NE is reorganized at specific sites with a profound importance of phosphorylation-triggered distortion of the nuclear lamina. 110,111 The regulation of this step has first been mechanistically analyzed for cytomegaloviruses, 44,50,57,62 and the HCMV-encoded protein kinase pUL97 was identified as the first herpesviral kinase with lamin-phosphorylating activity.…”

“…It is obvious that steric inhibitors of NEC subunit assembly, either blocking the interaction of core NEC or multimeric NEC-associated factors, may have great potential for pharmacological development. 98,107,108,132 Moreover, alternative mechanisms of NEC inhibition could be similarly effective, eg, the inhibitory targeting of NEC phosphorylation. Considering the fact that most if not all of the NEC-associated proteins undergo phosphorylation, inhibitors of NEC phosphorylation appear likewise attractive for use in antiviral applications.…”

Fantastic nuclear envelope herniations and where to find them

“…For example, herpesvirus exits the nucleus by budding through the NE lumen/PNS[91,92](Figure 3). While the molecular machinery that drives herpesvirus egress is encoded by the viral genome (the nuclear egress complex/NEC) and is thus distinct from NPC biogenesis, there is nonetheless evidence for the involvement of ESCRTs[93,94] and Torsin A[95] (and LULL1[96]) in the viral lifecycle hinting at a functional relationship with host nuclear membrane remodeling pathways.…”