Human Cytomegalovirus Egress: Overcoming Barriers and Co-Opting Cellular Functions

Abstract

The assembly of human cytomegalovirus (HCMV) and other herpesviruses includes both nuclear and cytoplasmic phases. During the prolonged replication cycle of HCMV, the cell undergoes remarkable changes in cellular architecture that include marked increases in nuclear size and structure as well as the reorganization of membranes in cytoplasm. Similarly, significant changes occur in cellular metabolism, protein trafficking, and cellular homeostatic functions. These cellular modifications are considered integral in the efficient assembly of infectious progeny in productively infected cells. Nuclear egress of HCMV nucleocapsids is thought to follow a pathway similar to that proposed for other members of the herpesvirus family. During this process, viral nucleocapsids must overcome structural barriers in the nucleus that limit transit and, ultimately, their delivery to the cytoplasm for final assembly of progeny virions. HCMV, similar to other herpesviruses, encodes viral functions that co-opt cellular functions to overcome these barriers and to bridge the bilaminar nuclear membrane. In this brief review, we will highlight some of the mechanisms that define our current understanding of HCMV egress, relying heavily on the current understanding of egress of the more well-studied α-herpesviruses, HSV-1 and PRV.

‘Come together’—The Regulatory Interaction of Herpesviral Nuclear Egress Proteins Comprises Both Essential and Accessory Functions

“…Since the diameter of herpesviral capsids is approximately 130 nm [ 1 ], herpesviruses have emerged as a specific mechanism, the so-called regulated nuclear egress, to bypass this barrier in a finely coordinated manner ( Figure 1 ). Thus, the nuclear egress is a crucial step during the late phase of replication and is conserved among α-, β- and γ-herpesviruses [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

“…As a characteristic feature of herpesviruses, the viral nuclear egress is a highly coordinated, multistep regulatory process. In this regard, the herpesviral NEC is a fascinating example of how a viral heterodimeric element (i.e., the core NEC) can provide a scaffold that hijacks host-specific functions including protein transport and intracellular trafficking [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 16 ]. Considering the specific case of HCMV, a central mechanistic determinant of nuclear egress is given by the multi-interacting pUL50, which is anchored to the nuclear membrane through its transmembrane domain (TMD).…”

Human Cytomegalovirus Nuclear Egress Complex Subunit, UL53, Associates with Capsids and Myosin Va, but Is Not Important for Capsid Localization towards the Nuclear Periphery

“…Newly assembled herpesvirus capsids translocate from the nucleus to the cytoplasm in a complicated process known as nuclear egress. Nuclear egress includes four distinct steps: (1) migration of capsids from the nuclear interior, where viral genome replication and encapsidation occur within discrete replication compartments (RCs), to the nuclear rim; (2) disruption of the nuclear lamina providing access to the inner nuclear membrane (INM): (3) budding of capsids through the INM (primary envelopment); and (4) de-envelopment at the outer nuclear membrane (reviewed in [ 1 , 2 , 3 , 4 ]).…”

“…The HCMV NEC recruits the viral protein kinase, UL97, to the nuclear rim for phosphorylation and thus disruption of the nuclear lamina [ 10 , 11 ]. Based on work with other herpesvirus NECs, the HCMV NEC also likely orchestrates capsid budding during primary envelopment (reviewed in [ 1 , 2 , 3 , 4 ]). However, there is evidence that nucleoplasmic subunits of certain herpesvirus NECs participate in processes upstream of events at the nuclear rim, such as DNA packaging, and capsid migration to the nuclear periphery [ 12 , 13 , 14 , 15 , 16 ].…”

UL34 Deletion Restricts Human Cytomegalovirus Capsid Formation and Maturation

“…Nuclear egress of the mature genome-containing capsids relies on both host and viral processes. The viral nuclear egress complex (NEC) consisting of UL50 and UL53 is essential, as is the breakdown of the nuclear lamina by phosphorylation by UL97 kinase and likely host CDK1 to allow capsids access to the nuclear membrane [ 28 ]. Capsids traverse both nuclear membranes in the process of envelopment and de-envelopment and enter the cytoplasm for further maturation.…”