1 Introduction
Cytomegaloviruses (CMV) cause productive, persistent or latent infections in their hosts. Productive infection requires the establishment of a complete manufacturing chain in the nucleus and cytosol for the successful production and release of infectious virions. This establishment is associated with overproduction of virus-encoded proteins and extensive reorganization of host cell pathways. The cytoplasmic part of the manufacturing chain involves a complex reorganization of the membrane system into a large structure known as the assembly compartment (AC), which adjusts the membrane composition to concentrate all essential components for the final stage of virion production known as the secondary envelopment and provides the exit pathway for the release of assembled virions from the cell (Wofford et al., 2020). These crucial steps in the CMV life cycle (Supplementary Figure S1) are still poorly understood and need to be regularly reconciled with advances in herpesvirus biology and membrane trafficking.
2 Cytoplasmic assembly compartment
The extensive reorganization of the membrane system has been investigated in several electron microscopy (EM) (Maninger et al., 2011; Schauflinger et al., 2013; Read et al., 2019; Taisne et al., 2019; Momtaz et al., 2021; Flomm et al., 2022; Wedemann et al., 2022) and immunofluorescence-based studies (Supplementary Table S1). This reorganization involves displacement the Golgi stacks into a ring-like configuration (outer AC) which surrounds the expanded membranous elements (inner AC), mainly the intermediates of the interface between early endosomes, the endosomal recycling compartment, and the trans-Golgi network (EE-ERC-TGN) (Das et al., 2007; Lučin et al., 2020). The overall structure relocates late endosomes (LE) and the endoplasmic reticulum (ER) to the cell periphery. Membrane expansion in the inner AC is associated with extensive tubulation and sustained recruitment of tubulation machinery. In addition, the AC is rich in vacuolized membrane structures that are often loaded with enveloped virions.
An important goal of membrane reorganization is to create a suitable environment for membrane envelopment of the nucleocapsids and to pave the exit pathway for the enveloped virions. These changes, initiated in the early phase of infection and completed after viral DNA replication, include redistribution and over-recruitment of proteins that regulate membrane trafficking (Beltran et al., 2016; Cook and Cristea, 2019; Lučin et al., 2020), alteration of lipid composition (Liu et al., 2011), retention of membrane trafficking and inhibition of endosomal recycling (Tomaš et al., 2010; Hook et al., 2014; Karleuša et al., 2018; Maschkowitz et al., 2018), and even establishment of heterotypic membranous organelles within the endosomal system in the post-sorting phase of endosomes (Cepeda et al., 2010; Zeltzer et al., 2018). However, little is known about the biogenesis and membrane composition of thousands of membranous units that make up the AC.
At least 14 virus-encoded tegument proteins and 11 glycoproteins are embedded in virions during the secondary envelopment (Varnum et al., 2004), and their concentration at the envelopment organelle is required. Studies focusing on the trafficking of highly conserved glycoproteins (including the gB, gH/gL/gO and gM/gN complexes) (Tugizov et al., 1999; Jarvis et al., 2002; Crump et al., 2003; Krzyzaniak et al., 2009; Maschkowitz et al., 2018) revealed their different maturation pathways. They concentrate in the trans-Golgi and circulate via different routes through the PM, endosomes and TGN. Several studies suggest that the clathrin-dependent endocytic uptake of viral glycoproteins, their delivery into the endosomal system and retrieval at the recycling membranes may be essential for the process of secondary envelopment (Krzyzaniak et al., 2009; Kropff et al., 2010; Wu et al., 2020). The identification of endosomal host cell cargo proteins (i.e., MHC class I proteins and Lamp1), several Rab GTPases (i.e., Rabs 12, 18, 23, and 32), cargo sorting proteins (i.e., sorting nexins 2 and 3), SNARE proteins (i.e., STX12, VAMP2, and VAMP3), and lipid-modifying proteins (i.e., PIK3C2A) as host cell membrane signatures that remain in virions (Mahmutefendić Lučin et al., 2022), support the idea that the distant stage of EE maturation in one of the endosomal recycling pathways may provide the retrieval machinery required for retention of viral glycoproteins. On the other hand, little is known about the concentration of tegument proteins, but they may be retained at the envelopment membrane by direct interaction with the retrieval machinery or by complex formation with retrieved glycoproteins (Seo and Britt, 2006; Wu et al., 2020).
3 Secondary envelopment
The EM studies agree that secondary envelopment occurs within the AC. Enveloped capsids have been observed as single capsids, but the hallmark of CMV infection is their accumulation in large vesicles, often referred to as MVBs or, better, multiviral bodies (MViBs), as recently proposed (Wedemann et al., 2022). Some CMVs, such as murine CMV in fibroblasts, are enveloped as large multicapsid virions (Maninger et al., 2011).
The identity of the envelopment membranes and the mechanism of CMV envelopment are still unknown. Studies of the trafficking of viral envelope proteins point to the trans-Golgi (Jarvis et al., 2002; Homman-Loudiyi et al., 2003; Cepeda et al., 2010), EEs (Tooze et al., 1993; Radsak et al., 1996; Fraile-Ramos et al., 2002), and the ERC (Krzyzaniak et al., 2009; Lučin et al., 2018; Lučin et al., 2020). There are also several lines of evidence that CMV maturation occurs within the membranous system along endocytic flux (Archer et al., 2017; Hasan et al., 2018; Štimac et al., 2021). Knockdown of host cell factors regulating membrane flux suggests that EE maturation is essential for virion envelopment and release (Sharon-Friling and Shenk, 2014; Pavelin et al., 2017; Turner et al., 2020).
Secondary envelopment is initiated by the contact of tegumented capsids with the membranous compartment, causing the membrane to deform and wrap around either as a double membrane or as budding into a larger compartment (Close et al., 2018; Wofford et al., 2020). Advanced EM has shown that CMV envelopment occurs at complex tubular structures that provide sufficient membranes to wrap around the capsids (Maninger et al., 2011; Schauflinger et al., 2013). These events are evenly distributed across the AC, and no preferred site for envelopment has been identified. At a later stage of infection, capsids were observed in large vacuoles at the periphery of the AC, leading to the proposal that envelopment occurs by budding in MVBs (Fraile-Ramos et al., 2002; Flomm et al., 2022; Wedemann et al., 2022). However, suppression of components of the endosomal sorting complex required for transport (ESCRT), which is essential for reverse budding into MVBs and MVB maturation toward the degradation pathway, did not affect CMV maturation (Fraile-Ramos et al., 2007), but further studies showed that the ESCRT-III machinery is involved in the final steps of HCMV replication (Tandon et al., 2009), likely in virion release and virus spread (Streck et al., 2018). A recent study demonstrates that ESCRT-III component CHMPC may be either required for scission of a pool of wrapping membranes derived from recycling endosomes used for envelopment of HSV1 or closure of membranes around virions analogous to the sealing of phagophore in autophagy (Russell et al., 2021). Proteomic and lipidomic analysis of extracellular virions identified several host cell signatures within virions that suggests envelopment at membranes derived from recycling EEs and did not reveal any signatures that might indicate envelopment at MVBs (Mahmutefendić Lučin et al., 2022). Thus, there is little evidence that MVBs can be used for envelopment.
4 Egress route
Alpha-herpesviruses exit cells as single particles via secretory vesicles and exosomes (Bergeman et al., 2023), whereas beta- (Bughio et al., 2015; Momtaz et al., 2021) and gamma-herpesviruses (Peng et al., 2010) appear to collect in large MVB-like membranous organelles before exiting cells. The exit of CMVs has been recently described as intermittent bulk release of many particles that attach to PM prior release into the extracellular fluid (Flomm et al., 2022; Wedemann et al., 2022). Virion-containing MVBs have been observed in several cell types and appear to represent a form of the non-conventional secretion pathway (Turner et al., 2020; Flomm et al., 2022). In fibroblasts, they are likely generated from classical LEs, whereas in endothelial cells they originate from a nonclassical Golgi-mediated exit pathway (Momtaz et al., 2021). The pathway by which enveloped virions are collected and the biogenesis of multivesicular organelles associated with CMV infection remain poorly understood. It is also not known whether CMVs can also envelop into single vesicles and be released as single virions by direct fusion with the PM, as suggested by (Turner and Mathias, 2022).
5 Discussion and further directions
The available information is insufficient to reconstruct the secondary envelopment and exit pathways of CMVs and should be reconciled with the growing knowledge of multiple sorting pathways at the EE-ERC-TGN interface, heterogeneity and redundancy of secretory pathways, and their overlap with secretory autophagy pathways. With this in mind, we propose the following scheme of BHV maturation (Figure 1) and highlight critical steps that should be clarified to fully understand BHV envelopment and egress.
FIGURE 1
To form the secondary envelopment site, CMVs should adapt protein and lipid composition that can concentrate envelope and tegument proteins and engulf large tegumented virions (multicapsids in the case of MCMV) into membrane organelle. For concentrating envelope proteins, CMVs can co-opt cargo sorting and retrieval machinery (i.e., sorting nexins, retrieving complexes), a function mostly associated with EEs. Envelopment can occur after the retrieval at membranes that can grow and bend around tegumented capsids, a property that characterize endosomal tubulation. Indeed, high membrane tubulation is a hallmark within the AC (Lučin et al., 2018; Lučin et al., 2020) and may be required for autophagosome-like membrane wrapping around tegumented capsids. However, no single biochemical remnant can be found in released virions as a signature of the conventional autophagy pathway, and on the other hand, many signatures found suggest envelopment at RE-derived membranes (Mahmutefendić Lučin et al., 2022). What triggers membrane wrapping around tegumented capsids remains unknown, and one mechanism could be the formation of tegument-initiated biomolecular condensates at the site of glycoprotein and nucleocapsid concentration, as has been proposed for herpes simplex virus (Metrick et al., 2020). In addition to protein machinery, lipid composition should also facilitate expansion and wrapping of the envelopment membranes. In the inner AC, membranes are rich in phosphatidylserine (PS) (Lučin et al., 2020), a cylindrical phospholipid required for elongation and PS should be replaced by conical phospholipids such as phosphatidylethanolamine (PE), which facilitates negative curvatures (McMahon and Boucrot, 2015). Indeed, proteomic (Turner et al., 2020) and lipidomic (Liu et al., 2011) analyses of virions revealed the absence of phosphoinositides, PS and PS-binding proteins, and enrichment of PE and PE-binding proteins.
Although envelopment on MVB-like structures has been proposed (Flomm et al., 2022), remnants of the machinery that drives the EE to LE maturation, sorts proteins into intralumenal vesicles, and performs the reverse budding process (i.e., ESCRT) on MVBs have been found in virions (Mahmutefendić Lučin et al., 2022). Most LE-derived MVB structures are dislocated outside the AC (Supplementary Table S1; (Lučin et al., 2020), and most envelopment events occur within the AC (Schauflinger et al., 2013). Nevertheless, envelopment on large organelles cannot be ruled out if forces other than the reverse budding machinery are responsible for envelopment. The ESCRT-III may contributes to the final stages Click or tap here to enter text and may be essential for membrane sealing in the wrapping processes, as in autophagosome maturation (Jiang et al., 2021).
To find a way out of the cell, CMV-containing vesicles should fuse with large transport vehicles that travel to the cell surface, as traveling within large MViBs appears to be the main exit route (Flomm et al., 2022). CMV-containing vesicles can fuse either with the continuous stream of large multivesicular organelles known as amphisomes that transport secretory autophagic contents out of the cell (Ganesan and Cai, 2021), or with degradative amphisomes and divert their route to the PM by delivering RE-derived factors, or even with LE- or TGN-derived vessels that form lysosome-related organelles (LRO) (Delevoye et al., 2019). It appears that the large vessels that transport CMV for release are heterogeneous: In fibroblasts, they are more associated with the LE-derived secretory pathway, whereas in endothelial cells, they correspond more to the autophagic pathway (Momtaz et al., 2021). In addition, virion-loaded organelles can undergo a maturation process similar to that described for LRO and be released by a biphasically evoked exocytic mechanism controlled by the GTPases Rab3a/Rab15/Rab35, as described for LRO (Biesemann et al., 2017), or by exocyst and Rab11b as for lysosome-associated exocytosis (Escrevente et al., 2021).
In conclusion, to understand the final steps of CMV production, it would be important to identify the envelopment organelle and the organelle that transports virions out of the cell. The roadmap requires identification of small GTPases (Rab proteins or others), tethering complexes, and SNARE proteins in both organelles. To achieve this, fluorescently labeled capsids would need to be observed throughout the infected cell over a long period of time, using live cell imaging technology with high resolution and very low phototoxicity. This appears to be a difficult task for CMV, and there are only a few reports (Sampaio et al., 2005; Bosse et al., 2012) on capsid-labeled virions. An additional obstacle for more in-depth studies is the heterogeneity of cells, which allows the establishment of the final steps of the assembly chain only in a limited number of cells. Therefore, cytoplasmic MViB transport appears to be a relatively rare event, and single-cell analyzes with labeled capsids are essential for further progress in the field of secondary envelopment and egress of CMVs.
Unlike alpha-herpesviruses and other viruses, CMV extensively remodel the cell’s membrane system to form unique compartments for their envelopment, egress, and possibly signaling (Henaff et al., 2012). Understanding these changes may therefore not only contribute to a better understanding of CMV biology, but also to elucidating the physiology of the membrane system. Accordingly, a detailed understanding of these processes would pave the way for further development of host-directed antiviral therapy, an emerging concept to develop broad-spectrum drugs to counteract the evolution of viral resistance (Kumar et al., 2020).
Statements
Author contributions
PL: Conceptualization, Formal Analysis, Funding acquisition, Project administration, Resources, Supervision, Validation, Visualization, Writing–original draft, Writing–review and editing. HML: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Writing–review and editing. GBZ: Funding acquisition, Investigation, Methodology, Writing–review and editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Croatian Science Foundation (Grants IP-2014-9-9564 and IP-2019-4-3582 to PL, IP-2020-02-2916 to HML, and IP-2020-02-1323 to GBZ), and by the University of Rijeka grants (uniri-biomed-18-88 to PL, uniri-biomed-18-180 to HML, uniri-biomed-18-229 to GBZ).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcell.2023.1328751/full#supplementary-material
References
1
ArcherM. A.BrechtelT. M.DavisL. E.ParmarR. C.HasanM. H.TandonR. (2017). Inhibition of endocytic pathways impacts cytomegalovirus maturation. Sci. Rep.7, 46069. April. 10.1038/srep46069
2
BeltranP. M. J.MathiasR. A.CristeaI. M.BeltranP. M. J.MathiasR. A.CristeaI. M. (2016). A Portrait of the human organelle proteome in Space and time during cytomegalovirus infection. Cell Syst.3, 361–373. 10.1016/j.cels.2016.08.012
3
BergemanM. H.HernandezM. Q.DiefenderferJ.DrewesJ. A.VelardeK.TierneyW. M.et al (2023). Live-cell fluorescence microscopy of HSV-1 cellular egress by exocytosis. BioRxiv. Available at: https://www.biorxiv.org/content/10.1101/2023.02.27.530373v2.
4
BiesemannA.GorontziA.BarrF.GerkeV. (2017). Rab35 protein regulates evoked exocytosis of endothelial Weibel–Palade bodies. J. Biol. Chem.292 (28), 11631–11640. 10.1074/jbc.M116.773333
5
BosseJ. B.BauerfeindR.PopilkaL.MarcinowskiL.TaeglichM.JungC.et al (2012). A beta-herpesvirus with fluorescent capsids to study transport in living cells. PLoS ONE7 (7), e40585. 10.1371/journal.pone.0040585
6
BughioF.UmashankarM.WilsonJ.GoodrumF. (2015). Human cytomegalovirus UL135 and UL136 genes are required for postentry tropism in endothelial cells. J. Virology89 (13), 6536–6550. 10.1128/JVI.00284-15
7
CepedaV.EstebanM.Fraile-RamosA. (2010). Human cytomegalovirus final envelopment on membranes containing both trans-Golgi network and endosomal markers. Cell. Microbiol.12 (3), 386–404. 10.1111/j.1462-5822.2009.01405.x
8
CloseW. L.AndersonA. N.PellettP. E. (2018). “Betaherpesvirus virion assembly and egress,” in Advances in experimental medicine and biology (vol. 1045, pp. 167–207) (New York: Springer New York LLC), 167–207. 10.1007/978-981-10-7230-7_9
9
CookK. C.CristeaI. M. (2019). Location is everything: protein translocations as a viral infection strategy. Curr. Opin. Chem. Biol.48, 34–43. 10.1016/j.cbpa.2018.09.021
10
CrumpC. M.HungC.-H.ThomasL.WanL.ThomasG. (2003). Role of PACS-1 in trafficking of human cytomegalovirus glycoprotein B and virus production. J. Virology77 (20), 11105–11113. 10.1128/JVI.77.20.11105-11113.2003
11
DasS.VasanjiA.PellettP. E. (2007). Three-dimensional structure of the human cytomegalovirus cytoplasmic virion assembly complex includes a reoriented secretory apparatus. J. Virology81 (21), 11861–11869. 10.1128/jvi.01077-07
12
DelevoyeC.MarksM. S.RaposoG. (2019). Lysosome-related organelles as functional adaptations of the endolysosomal system. Curr. Opin. Cell Biol.59, 147–158. 10.1016/j.ceb.2019.05.003
13
EscreventeC.Bento-LopesL.RamalhoJ. S.BarralD. C. (2021). Rab11 is required for lysosome exocytosis through the interaction with Rab3a, Sec15 and GRAB. J. Cell Sci.134 (11), jcs246694. 10.1242/JCS.246694
14
FlommF. J.SohT. K.SchneiderC.WedemannL.BrittH. M.ThalassinosK.et al (2022). Intermittent bulk release of human cytomegalovirus. PLoS Pathog.18 (8), e1010575. 10.1371/journal.ppat.1010575
15
Fraile-RamosA.Pelchen-MatthewsA.KledalT. N.BrowneH.SchwartzT. W.MarshM. (2002). Localization of HCMV UL33 and US27 in endocytic compartments and viral membranes. Traffic3 (3), 218–232. 10.1034/j.1600-0854.2002.030307.x
16
Fraile-RamosA.Pelchen-MatthewsA.RiscoC.RejasM. T.EmeryV. C.Hassan-WalkerA. F.et al (2007). The ESCRT machinery is not required for human cytomegalovirus envelopment. Cell. Microbiol.9 (12), 2955–2967. 10.1111/j.1462-5822.2007.01024.x
17
GanesanD.CaiQ. (2021). Understanding amphisomes. Biochem. J.478 (10), 1959–1976. 10.1042/BCJ20200917
18
HasanM. H.DavisL. E.BollavarapuR. K.MitraD.ParmarR.TandonR. (2018). Dynamin is required for efficient cytomegalovirus maturation and envelopment. J. Virology92 (24), e01418-18. 10.1128/JVI.01418-18
19
HenaffD.RadtkeK.LippéR. (2012). Herpesviruses exploit several host compartments for envelopment. Traffic13 (11), 1443–1449. 10.1111/j.1600-0854.2012.01399.x
20
Homman-LoudiyiM.HultenbyK.BrittW.Söderberg-NauclérC. (2003). Envelopment of human cytomegalovirus occurs by budding into golgi-derived vacuole compartments positive for gB, rab 3, trans-golgi network 46, and mannosidase II. J. Virology77 (5), 3191–3203. 10.1128/jvi.77.5.3191-3203.2003
21
HookL. M.GreyF.GrabskiR.TirabassiR.DoyleT.HancockM.et al (2014). Cytomegalovirus miRNAs target secretory pathway genes to facilitate formation of the virion assembly compartment and reduce cytokine secretion. Cell Host Microbe15 (3), 363–373. 10.1016/j.chom.2014.02.004
22
JarvisM. A.FishK. N.Söderberg-NauclerC.StreblowD. N.MeyersH. L.ThomasG.et al (2002). Retrieval of human cytomegalovirus glycoprotein B from cell surface is not required for virus envelopment in astrocytoma cells. J. Virology76 (10), 5147–5155. 10.1128/jvi.76.10.5147-5155.2002
23
JiangW.ChenX.JiC.ZhangW.SongJ.LiJ.et al (2021). Key regulators of autophagosome closure. Cells10 (11), 2814. 10.3390/CELLS10112814
24
KarleušaL.MahmutefendićH.TomašM. I. M. I.ZagoracG. B. G. B.LučinP. (2018). Landmarks of endosomal remodeling in the early phase of cytomegalovirus infection. Virology515, 108–122. 10.1016/j.virol.2017.12.001
25
KropffB.KoedelY.BrittW.MachM. (2010). Optimal replication of human cytomegalovirus correlates with endocytosis of glycoprotein gpUL132. J. Virology84 (14), 7039–7052. 10.1128/jvi.01644-09
26
KrzyzaniakM. A.MachM.BrittW. J. (2009). HCMV-encoded glycoprotein M (UL100) interacts with rab11 effector protein FIP4. Traffic10 (10), 1439–1457. 10.1111/j.1600-0854.2009.00967.x
27
KumarN.SharmaS.KumarR.TripathiB. N.BaruaS.LyH.et al (2020). Host-directed antiviral therapy. Clin. Microbiol. Rev.33 (3), e00168-19. 10.1128/CMR.00168-19
28
LiuS. T. H.Sharon-FrilingR.IvanovaP.MilneS. B.MyersD. S.RabinowitzJ. D.et al (2011). Synaptic vesicle-like lipidome of human cytomegalovirus virions reveals a role for SNARE machinery in virion egress. Proc. Natl. Acad. Sci. U. S. A.108 (31), 12869–12874. 10.1073/pnas.1109796108
29
LučinP.Jug VučkoN.KarleušaL.Mahmutefendić LučinH.Blagojević ZagoracG.LisnićB.et al (2020). Cytomegalovirus generates assembly compartment in the early phase of infection by perturbation of host-cell factors recruitment at the early endosome/endosomal recycling compartment/trans-Golgi interface. Front. Cell Dev. Biol.8, 563607. 10.3389/fcell.2020.563607
30
LučinP.KarelušaL.Blagojević ZagoracG.Mahmutefendić LučinH.PavišićV.Jug VučkoN.et al (2018). Cytomegaloviruses exploit recycling Rab proteins in the sequential establishment of the assembly compartment. Front. Cell Dev. Biol.6, 165. DEC. 10.3389/fcell.2018.00165
31
Mahmutefendić LučinH.Blagojević ZagoracG.MarcelićM.LučinP. (2022). Host cell signatures of the envelopment site within beta-herpes virions. Int. J. Mol. Sci.23 (17), 9994. 10.3390/IJMS23179994
32
ManingerS.BosseJ. B.LemnitzerF.PogodaM.MohrC. A.von EinemJ.et al (2011). M94 is essential for the secondary envelopment of murine cytomegalovirus. J. Virology85 (18), 9254–9267. 10.1128/jvi.00443-11
33
MaschkowitzG.GärtnerS.Hofmann-WinklerH.FickenscherH.WinklerM. (2018). Interaction of human cytomegalovirus tegument proteins ppUL35 and ppUL35A with sorting nexin 5 regulates glycoprotein B (gpUL55) localization. J. Virology92 (9), e00013-18. 10.1128/JVI.00013-18
34
McMahonH. T.BoucrotE. (2015). Membrane curvature at a glance. J. Cell Sci.128 (6), 1065–1070. 10.1242/JCS.114454
35
MetrickC. M.KoenigsbergA. L.HeldweinE. E. (2020). Conserved outer tegument component ul11 from herpes simplex virus 1 is an intrinsically disordered, rna-binding protein. MBio11 (3), e00810-20. 10.1128/mBio.00810-20
36
MomtazS.MolinaB.MleraL.GoodrumF.WilsonJ. M. (2021). Cell type-specific biogenesis of Novel vesicles containing viral products in human cytomegalovirus infection. J. Virology95 (11), e02358-20. 10.1128/jvi.02358-20
37
PavelinJ.McCormickD.ChiwesheS.RamachandranS.LinY. T.GreyF. (2017). Cellular v-ATPase is required for virion assembly compartment formation in human cytomegalovirus infection. Open Biol.7 (11), 160298. 10.1098/rsob.160298
38
PengL.RyazantsevS.SunR.ZhouZ. H. (2010). Three-dimensional visualization of gammaherpesvirus life cycle in host cells by electron tomography. Structure18 (1), 47–58. 10.1016/j.str.2009.10.017
39
RadsakK.EickmannM.MockenhauptT.BognerE.KernH.Eis-HübingerA.et al (1996). Retrieval of human cytomegalovirus glycoprotein B from the infected cell surface for virus envelopment. Archives Virology141 (3–4), 557–572. 10.1007/BF01718317
40
ReadC.SchauflingerM.NikolaenkoD.WaltherP.von EinemJ. (2019). Regulation of human cytomegalovirus secondary envelopment by a C-terminal tetralysine Motif in pUL71. J. Virology93 (13), e02244-18. 10.1128/jvi.02244-18
41
RussellT.SamolejJ.HollinsheadM.SmithG. L.KiteJ.ElliottG. (2021). Novel role for escrt-iii component chmp4c in the integrity of the endocytic network utilized for herpes simplex virus envelopment. MBio12 (3), e02183-20. 10.1128/mBio.02183-20
42
SampaioK. L.CavignacY.StierhofY.-D.SinzgerC. (2005). Human cytomegalovirus labeled with green fluorescent protein for live analysis of intracellular particle movements. J. Virology79 (5), 2754–2767. 10.1128/jvi.79.5.2754-2767.2005
43
SchauflingerM.VillingerC.MertensT.WaltherP.von EinemJ. (2013). Analysis of human cytomegalovirus secondary envelopment by advanced electron microscopy. Cell. Microbiol.15 (2), 305–314. 10.1111/cmi.12077
44
SeoJ.-Y.BrittW. J. (2006). Sequence requirements for localization of human cytomegalovirus tegument protein pp28 to the virus assembly compartment and for assembly of infectious virus. J. Virology80 (11), 5611–5626. 10.1128/jvi.02630-05
45
Sharon-FrilingR.ShenkT. (2014). Human cytomegalovirus pUL37x1-induced calcium flux activates PKCα, inducing altered cell shape and accumulation of cytoplasmic vesicles. Proc. Natl. Acad. Sci. U. S. A.111 (12), E1140–E1148. 10.1073/pnas.1402515111
46
ŠtimacI.VučkoN. J.ZagoracG. B.MarcelićM.LučinH. M.LučinP. (2021). Dynamin inhibitors prevent the establishment of the cytomegalovirus assembly compartment in the early phase of infection. Life11 (9), 876. 10.3390/life11090876
47
StreckN. T.CarmichaelJ.BuchkovichN. J. (2018). Nonenvelopment role for the ESCRT-III complex during human cytomegalovirus infection. J. Virology92 (12), e02096-17. 10.1128/jvi.02096-17
48
TaisneC.LussignolM.HernandezE.MorisA.MounaL.EsclatineA. (2019). Human cytomegalovirus hijacks the autophagic machinery and LC3 homologs in order to optimize cytoplasmic envelopment of mature infectious particles. Sci. Rep.9 (1), 4560. 10.1038/s41598-019-41029-z
49
TandonR.AuCoinD. P.MocarskiE. S. (2009). Human cytomegalovirus Exploits ESCRT machinery in the process of virion maturation. J. Virology83 (20), 10797–10807. 10.1128/jvi.01093-09
50
TomašM. I.KučićN.MahmutefendićH.BlagojevićG.LučinP. (2010). Murine cytomegalovirus perturbs endosomal trafficking of major histocompatibility complex class I molecules in the early phase of infection. J. Virology84 (21), 11101–11112. 10.1128/JVI.00988-10
51
ToozeJ.HollinsheadM.ReisB.RadsakK.KernH. (1993). Progeny vaccinia and human cytomegalovirus particles utilize early endosomal cisternae for their envelopes. Eur. J. Cell Biol.60 (1), 163–178.
52
TugizovS.MaidjiE.XiaoJ.PereiraL. (1999). An acidic cluster in the cytosolic Domain of human cytomegalovirus glycoprotein B is a signal for endocytosis from the plasma membrane. J. Virology73 (10), 8677–8688. 10.1128/jvi.73.10.8677-8688.1999
53
TurnerD. L.KorneevD. V.PurdyJ. G.de MarcoA.MathiasR. A. (2020). The host exosome pathway underpins biogenesis of the human cytomegalovirus virion. ELife9, 582888–e58329. 10.7554/ELIFE.58288
54
TurnerD. L.MathiasR. A. (2022). The human cytomegalovirus decathlon: ten critical replication events provide opportunities for restriction. Front. Cell Dev. Biol.10, 1053139. 10.3389/fcell.2022.1053139
55
VarnumS. M.StreblowD. N.MonroeM. E.SmithP.AuberryK. J.PasL.et al (2004). Identification of proteins in human cytomegalovirus (HCMV) particles: the HCMV proteome. J. Virology78 (20), 10960–10966. 10.1128/JVI.78.20.10960-10966.2004
56
WedemannL.FlommF. J.BosseJ. B. (2022). The unconventional way out-Egress of HCMV through multiviral bodies. Mol. Microbiol.117 (6), 1317–1323. 10.1111/MMI.14946
57
WoffordA. S.McCuskerI.GreenJ. C.VenskoT. A.PellettP. E. (2020). “Betaherpesvirus assembly and egress: recent advances illuminate the path,” in Advances in virus research. 1 (Amsterdam, Netherlands: Elsevier Inc). Vol. 108. 10.1016/bs.aivir.2020.09.003
58
WuH.KropffB.MachM.BrittW. J. (2020). Human cytomegalovirus envelope protein gpUL132 regulates infectious virus production through Formation of the viral assembly compartment. MBio11 (5), 020444-20–e2116. 10.1128/MBIO.02044-20
59
ZeltzerS.ZeltzerC. A.IgarashiS.WilsonJ.DonaldsonJ. G.GoodrumF. (2018). Virus control of trafficking from sorting endosomes. MBio9 (4), 006833-18–e718. 10.1128/mBio.00683-18
Summary
Keywords
betaherpesviruses, cytomegalovirus, assembly compartment, secondary envelopment, virion egress, multiviral bodies
Citation
Lučin P, Mahmutefendić Lučin H and Blagojević Zagorac G (2023) Cytomegaloviruses reorganize endomembrane system to intersect endosomal and amphisome-like egress pathway. Front. Cell Dev. Biol. 11:1328751. doi: 10.3389/fcell.2023.1328751
Received
27 October 2023
Accepted
08 December 2023
Published
19 December 2023
Volume
11 - 2023
Edited by
Roger Schneiter, University of Fribourg, Switzerland
Reviewed by
Wen Xiong, Baylor College of Medicine, United States
Philip E. Pellett, Wayne State University, United States
Updates
Copyright
© 2023 Lučin, Mahmutefendić Lučin and Blagojević Zagorac.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Pero Lučin, pero.lucin@uniri.hr, pero@uniri.hr
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.