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Review
. 2021 Mar 4;10(3):542.
doi: 10.3390/cells10030542.

Modulation of Endosome Function, Vesicle Trafficking and Autophagy by Human Herpesviruses

Eduardo I Tognarelli  1   2 , Antonia Reyes  1   2 , Nicolás Corrales  1   2 , Leandro J Carreño  1   3 , Susan M Bueno  1   2 , Alexis M Kalergis  1   4 , Pablo A González  1   2
Affiliations
Review

Modulation of Endosome Function, Vesicle Trafficking and Autophagy by Human Herpesviruses

Eduardo I Tognarelli et al. Cells. .

Abstract

Human herpesviruses are a ubiquitous family of viruses that infect individuals of all ages and are present at a high prevalence worldwide. Herpesviruses are responsible for a broad spectrum of diseases, ranging from skin and mucosal lesions to blindness and life-threatening encephalitis, and some of them, such as Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are known to be oncogenic. Furthermore, recent studies suggest that some herpesviruses may be associated with developing neurodegenerative diseases. These viruses can establish lifelong infections in the host and remain in a latent state with periodic reactivations. To achieve infection and yield new infectious viral particles, these viruses require and interact with molecular host determinants for supporting their replication and spread. Important sets of cellular factors involved in the lifecycle of herpesviruses are those participating in intracellular membrane trafficking pathways, as well as autophagic-based organelle recycling processes. These cellular processes are required by these viruses for cell entry and exit steps. Here, we review and discuss recent findings related to how herpesviruses exploit vesicular trafficking and autophagy components by using both host and viral gene products to promote the import and export of infectious viral particles from and to the extracellular environment. Understanding how herpesviruses modulate autophagy, endolysosomal and secretory pathways, as well as other prominent trafficking vesicles within the cell, could enable the engineering of novel antiviral therapies to treat these viruses and counteract their negative health effects.

Keywords: ESCRT; autophagy; endocytosis; exocytosis; human herpesviruses; lysosomes; trans-Golgi network; viral.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms used by human herpesviruses to enter host cells. (A) Clathrin-mediated entry for herpesviruses in general. Herpesviruses induce clathrin oligomerization, together with the recruitment of host factors and adapter proteins, which also induce the polimerization of actin filaments and lastly the invagination of the cell membrane, thanks to the GTPase activity of dynamin. (B) Cell entry mechanisms exploited by human herpesviruses type 1 and type 2 (HSV-1 and HSV-2). The binding of viral glycoproteins B and D to their ligands triggers dimerization of the gH/gL complex, which causes the activation of the fusogenic activity of gB, enabling the release of the viral capsid into the cytosol. On the other hand, viral capsid delivery through the endosomal pathway has also been described, which is associated with endosomes having a low pH. (C) The mechanism used by varicella-zoster virus (VZV) for entering cells is also mediated by the gH/gL complex, but clathrin-mediated entry has also been described for this virus. (D) The Epstein–Barr virus (EBV) has been described to enter the cell through its binding to the EPHA2 receptor. Alternatively, other entry pathways exist, such as that mediated by BMRF-2 binding to integrins, causing gH/gL complex activation and gB-mediated fusion of membranes; lipid raft-mediated endocytosis; or viral entry through micro- and micropinocytosis. (E) The human cytomegalovirus (HCMV) mainly enters the cell via the activation of the gH/gL complex, triggering gB-mediated membrane fusion, but a low pH-dependent endocytosis mechanism has also been reported, involving a viral protein complex binding to host OR14I1. (F) The entry mechanisms exploited by human herpesviruses 6 (HHV-6; HHV-6A and HHV-6B) mainly occurs by endocytosis through lipid rafts. (G) The only entry mechanism described so far for the human herpesvirus 7 (HHV-7) is mediated by a fusogenic process mediated by the gH/gL complex. No endocytic pathway has been described yet for this virus. (H) Finally, Kaposi’s sarcoma-associated herpesvirus (KSV) infects the cells through a gB-mediated membrane fusion pathway, clathrin-mediated endocytosis and may also induce micro- and macropinocytosis.
Figure 2
Figure 2
Modulation of autophagosome formation by herpesviruses. (A) Autophagosome formation in mammalian cells begins with the materialization of the phagophore, together with the recruitment of host proteins autophagy-related protein 13, ULK1 and ULK2. (B) Afterward, ULK1 phosphorylation activates the beclin-1 protein and triggers the recruitment of proteins that finally recruit the class-III phosphatidylinositol-3 kinase to the autophagosome membrane. The activation of beclin-1 is inhibited by the viral proteins BCL2, TRS1 and ICP34.5 of Kaposi’s sarcoma-associated herpesvirus (KSHV), human cytomegalovirus (HCMV) and herpes simplex virus (HSV), respectively. (C) The early autophagosome recruits the LC-3 protein, a process that is enhanced by VZV, which triggers the maturation of the autophagosome due to the lipidation of LC-3 into LC-3-II. The latter step has been shown to be enhanced by KSHV. (D) Ultimately, autophagy concludes with fusion of a mature autophagosome with a lysosome. This process has been shown to be inhibited by VZV and the protein RAB7A by KSHV.
Figure 3
Figure 3
Human herpesvirus infection affects lysosome- and Golgi-sorting vesicle functions. (A) Lysosome activity has been shown to be crucial for herpesviruses infection. HSV and HCMV increase the pH levels of lysosomes in order to inactivate them. UL21 from HHV-6 and HHV-7 bind to MHC-I host proteins and divert them toward lysosomal degradation. VZV internalization has been shown to be inhibited by lysomotropic agents, suggesting a key role for the lysosomal pathway in the infection process mediated by this virus. HSV-1 inhibits key steps related to lysosome activation, such as cathepsin maturation, hydrolase activity and the EGFG-mediated endocytic pathway. (B) Capsid envelopment and glycoprotein maturation of herpesviruses occur through the Golgi apparatus and the trans-Golgi network (TGN). The corresponding viral proteins are transported to the cell membrane and then internalized into endosomes. This process has been described to be enhanced by means of the RAB5A protein by HSV-1. Clathrin-coated vesicles are transported into the cytosol, where the adapter protein 1 (AP-1) has been shown to interact with the VP22 and ORF9b proteins of HSV-2 and VZV, respectively. HCMV modifies the TGN, forming a barrel-like structure at the cis and trans sides of the Golgi apparatus.
Figure 4
Figure 4
Exocytosis vesicles participate in herpesvirus exit. (A) The accumulation of herpesvirus capsids in the cytoplasm has been shown to be assisted by VAPB host proteins. (B) The HSV-1 Us9 protein interacts with capsids in the endoplasmic reticulum (ER), the Golgi apparatus and the cytosol in order to promote the anterograde transport of viral components through microtubules. Us3 protein has also been shown to stabilize and activate microtubules and CLASP complexes to promote vesicle transport. The interactions of viral gD with host M6P and its receptors promote the export of virus-containing late endosomes. On the other hand, viral proteins have been shown to co-localize with CD63 or CD63 and MHC-II, suggesting a potential immune-modulatory role for late endosomal trafficking. (C) VZV has been reported to use M6P and its receptors to promote viral export. Additionally, this virus appears to be exocytosed in single-membrane vesicles from the autophagosomal pathway, which contain LC-3 and Rab II. (D) EBV shuttles LPMI- and miRNA-containing vesicles derived in exosomal traffic modulation. (E) Exit of HHV-6 occurs through the exosomal pathway, using multivesicular bodies (MVBs). (F) Finally, KSHV recycles clathrin-coated endosomal vesicles, used during cell entry, for viral exit using the viral protein ORF65.
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References

    1. Rajsbaum R., García-Sastre A. Viral evasion mechanisms of early antiviral responses involving regulation of ubiquitin pathways. Trends Microbiol. 2013;21:421–429. doi: 10.1016/j.tim.2013.06.006. - DOI - PMC - PubMed
    1. Yamauchi Y., Helenius A. Virus entry at a glance. J. Cell Sci. 2013;126:1289–1295. doi: 10.1242/jcs.119685. - DOI - PubMed
    1. Lee H.-C., Chathuranga K., Lee J.-S. Intracellular sensing of viral genomes and viral evasion. Exp. Mol. Med. 2019;51:1–13. doi: 10.1038/s12276-019-0299-y. - DOI - PMC - PubMed
    1. Tognarelli E.I., Palomino T.F., Corrales N., Bueno S.M., Kalergis A.M., González P.A. Herpes Simplex Virus Evasion of Early Host Antiviral Responses. Front. Cell. Infect. Microbiol. 2019;9:127. doi: 10.3389/fcimb.2019.00127. - DOI - PMC - PubMed
    1. Taylor M.P., Koyuncu O.O., Enquist L.W. Subversion of the actin cytoskeleton during viral infection. Nat. Rev. Genet. 2011;9:427–439. doi: 10.1038/nrmicro2574. - DOI - PMC - PubMed

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