autophagy and viruses

Inhibition of the antiviral autophagic mechanism has also been reported. Keywords: Autophagy certainly acts as both an anti-viral and pro-viral pathway, and the roles of autophagy depend on the virus, the cell type, and the cellular environment. Unable to load your collection due to an error, Unable to load your delegates due to an error. The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase. Subsequently, the Bcl-2 homolog of HV68 was also reported to inhibit autophagy by interaction with Beclin 1 [86,87]. The UPR, which is induced by the accumulation of unfolded proteins in the ER, includes the activation of PERK and transcription factor 6 (ATF6), and the induction of inositol requiring kinase 1 (IRE-1). reported that the growth of an ICP34.5 deletion mutant virus was defective in normal cells, whereas in PKR/ MEFs, replication of this mutant virus could be restored [44]. Moreover, viruses can exploit autophagy-related proteins in an autophagy-independent manner. CD46, which is well known to act as a receptor for several pathogens, has been reported very recently to induce autophagy via a pathway involving the Beclin 1 complex after measles virus infection [79]. Rather, this review is organized around general themes regarding the relationship between autophagy and animal viruses. Hurtado-Tamayo J, Requena-Platek R, Enjuanes L, Bello-Perez M, Sola I. Would you like email updates of new search results? Sinha S, Colbert CL, Becker N, Wei Y, Levine B. Molecular basis of the regulation of Beclin 1-dependent autophagy by the gamma-herpesvirus 68 Bcl-2 homolog M11. Consequently, FLIP prevents the conjugation of LC3 which is essential for autophagic vesicle expansion. Autophagy acts as both an anti-viral and pro-viral pathway. Organization of the pre-autophagosomal structure responsible for autophagosome formation. 2023 Mar 21;12(6):956. doi: 10.3390/cells12060956. Mizushima N, Noda T, Ohsumi Y. Apg16p is required for the function of the Apg12p-Apg5p conjugate in the yeast autophagy pathway. and Y.C. Us11 (HSV-1) blocks PKR directly in the late stages of infection. This had already been reported previously, but had been attributed to the role of ICP34.5 in inhibiting PKR-dependent host cell shutoff [60]. What we know so far about the relationship between autophagy and viruses is summarized. 2023 May 19;21(1):114. doi: 10.1186/s12964-022-01026-8. J Mol Biol. have also reported that autophagy is involved in the presentation of the viral glycoprotein gB to CD8+ T cells by MHC class I, in collaboration with the canonical ER-dependent pathway [47]. The conjugation of LC3 (detected by Western blot analysis), and the membrane localization of lipidated LC3 (detected by fluorescent microscopy) are the usual markers of early autophagy [21]. Structural and biochemical bases for the inhibition of autophagy and apoptosis by viral BCL-2 of murine gamma-herpesvirus 68. Autophagy is a highly conserved intracellular degradation process that targets protein aggregates and damaged organelles. 2008 Apr;4(3):280-5. doi: 10.4161/auto.5289. Mercer CA, Kaliappan A, Dennis PB. Following viral infection, autophagy is often initiated to curtail infection by delivering viral particles for lysosomal degradation and further integrating with innate pattern recognition receptor signaling to induce interferon (IFN)-mediated viral clearance. Bookshelf (ii) The Beclin 1:hVps34 macromolecular complex is required for the nucleation, and assembly of the initial phagophore membrane (Figure 1). A selective autophagy receptor VISP1 induces symptom recovery Accessibility Cheong H, Yorimitsu T, Reggiori F, Legakis JE, Wang CW, Klionsky DJ. Zika virus triggers autophagy to exploit host lipid metabolism and 2023 Apr 27;97(4):e0026423. Nothing is yet known about the interplay between autophagy and the lytic cycle of EBV, but at least two latent antigens, EBNA 1 and LMP1, are known to activate or to interfere with the autophagic machinery [48,80]. Clipboard, Search History, and several other advanced features are temporarily unavailable. 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Shown are selected examples of proviral functions of autophagy-related genes and representative viruses that may benefit from such proviral functions. Some autophagy proteins are targeted by Herpesvirus-encoded proteins. Cellular autophagy: surrender, avoidance and subversion by microorganisms. Autophagy can support EV-A71 replication in human cell lines. Taylor MP, Burgon TB, Kirkegaard K, Jackson WT. reported that xenophagy plays a role in degrading HSV-1 virions, based on the presence of virions visualized by electron microscopy inside autophagosomes, and on the accelerated degradation rate of viral proteins after infection with an ICP34.5 deletion mutant [44]. Interestingly, the HSV-1 Us11 gene is also dedicated to regulating the PKR eIF2 signaling pathway [64,65]. Some viruses induce autophagy at the earliest stages of their life cyclesmeasles virus (MeV) induces autophagy through binding to CD46, a cell surface receptor required for MeV entry . Vesicular trafficking and autophagosome formation. LMP1 is expressed at a wide range of levels in B-cells originating from the same clone, and Lee and Sugden showed that this variation controls the induction of different signaling pathways: intermediate levels of LMP1 expression are required for B-cell proliferation to occur, whereas higher levels induce the unfolded protein response (UPR), by activating the PKR-like endoplasmic reticulum-related kinase (PERK) [85]. Autophagy is a protein degradative process important for normal cellular metabolism. Autophagy and Viral Infection - PMC - National Center for Biotechnology Ad Is autophagy good or bad for your health? These latest observations tend to suggest that autophagy does not in fact have any impact on the viral replication cycle in cell cultures, and so cannot be responsible for the growth defect of the ICP34.5 deletion mutant virus. 2023 Jul 8;14(7):409. doi: 10.1038/s41419-023-05929-3. Recent topics related to human herpesvirus 6 cell tropism. This complex consists of the class III phosphatidylinositol 3-kinase (PI3K) (or hVps34), its regulatory protein kinase p150 or hVps15, Beclin 1 (Atg6 in yeast), and Atg14L (or Barkor and Atg14 in yeast) [13,14]. The LMP1 oncogene of EBV activates PERK and the unfolded protein response to drive its own synthesis. Autophagy and Viruses: Adversaries or Allies? - Karger Publishers Klionsky DJ, Cregg JM, Dunn WA, Jr, Emr SD, Sakai Y, Sandoval IV, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y. Kawamata T, Kamada Y, Kabeya Y, Sekito T, Ohsumi Y. HCMV may inhibit autophagy via mTOR activation. Atg14L recruits the complex to the autophagosomal membrane, and is necessary for autophagosome formation, whereas the Beclin 1:hVps34:p150 complex formed with UVRAG is involved in autophagosome and endosome maturation. Autophagy. Moreover, to survive and propagate within the host, viruses have evolved a variety of strategies to evade autophagic attack and manipulate the autophagy machinery for their own benefit. Before Talloczy Z, Jiang W, Virgin HWt, Leib DA, Scheuner D, Kaufman RJ, Eskelinen EL, Levine B. Autophagy is a powerful tool that host cells use to defend against viral infection. Bethesda, MD 20894, Web Policies Before The ability of xenophagy to capture and eliminate new incoming HSV-1 virions therefore remains to be demonstrated. eCollection 2023. In conclusion, it becomes clear that most animal viruses, including porcine and avian viruses, induce autophagy to promote virus replication, suggesting that during long-term . Autophagy is an evolutionarily conserved cellular degradation pathway involving the digestion of intracellular components via the lysosomal pathway. Apoptosis is used by host cells as part of their antiviral response, and impairs virus production by triggering premature cell death. Viruses can exploit autophagy or the autophagy machinery to facilitate their infection. On one hand, autophagy destructs viruses, regulates inflammatory responses, and provokes antigen presentation. McCormick AL. New agents that specifically target autophagy will have to be developed to test this potential new antiviral approach. Single autophagy proteins or cassettes of the core autophagy machinery can also function as antiviral factors independently of the canonical autophagy pathway. PKR is a key player in the antiviral action of interferon, and many viruses express proteins that antagonize the PKR signaling pathway [39]. Interestingly, several studies have reported the induction of autophagy by ER stress, notably after activation of eIF2 by PERK, thus linking autophagy to the UPR [37,40]. Complete sequence and genomic analysis of murine gammaherpesvirus 68. Under these conditions, the upregulation of autophagy enables the cell to survive by providing amino acids and energy, by clearing damaged proteins and organelles, and by eliminating intracellular pathogenic microbes via a process known as xenophagy. It is noteworthy that HHV-6 uses human CD46 as a cellular receptor during fusion with and entry into target cells [78]. Interestingly, the autophagic protein Beclin 1, which was initially identified as a Bcl-2 interacting protein (35), has also been reported to interact with ICP34.5 in a yeast two-hybrid screen using ICP34.5 as bait (B. Roizman, personal communication). Cassady KA, Gross M. The herpes simplex virus type 1 U(S)11 protein interacts with protein kinase R in infected cells and requires a 30-amino-acid sequence adjacent to a kinase substrate domain. National Library of Medicine VZV is in fact known to remain highly cell-associated in cell cultures, and enveloped virions accumulate in acidic cytoplasmic vacuoles other than lysosomes, which means that autophagy might limit viral production by trapping viral particles in the autophagosomal pathway. During autophagy, part of the cytoplasm is engulfed by a double membrane (the isolation membrane), which first elongates and then closes to form the autophagosome (Figure 1). We treated Nsp12-Myc-transfected cells with another lysosome inhibitor, bafilomycin A1 (BafA1), and evaluated the levels of microtubule-associated protein 1 light chain 3 (MAP1LC3/LC3), a marker of autophagy ( 19 ). Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH, Goldberg AL. FLIP expression prevented autophagic cell death induced by rapamycin, hinting that autophagy inhibition may be relevant for in vivo HHV-8 pathogenesis [88]. Downregulation of autophagy by herpesvirus Bcl-2 homologs. Coronavirus interactions with the cellular autophagy machinery Indeed, a recent paper has reported that the neurovirulence of the Beclin 1-binding-deficient ICP34.5 mutant virus was completely restored in mice lacking functional T and B cells, clearly connecting autophagy to the control of adaptative immune response [68]. FOIA Starvation leads to dissociation of the cellular Bcl-2-Beclin 1 complex as a result of the phosphorylation of cBcl-2 by activated JNK1, and consequently an induction of autophagy [31]. Careers, Unable to load your collection due to an error. Inhibition of autophagy has also been reported in HIV-infected CD4 T-lymphocytes [50]. Autophagy plays an important role when it comes to aging and longevity, too. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 2021 Jun 24;26(1):29. doi: 10.1186/s11658-021-00272-x. Autophagy is an evolutionarily conserved catabolic cellular process that exerts antiviral functions during a viral invasion. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. Kidney cells infected by a mutant BHV-1 virus lacking bovine Infected Cell Protein 0 (bICP0) displayed more autophagosomes than cells infected with the wild-type virus, indicating that bICP0 might antagonize autophagy [70]. Curr Opin Virol. They serve as organs in your body but within your cells. Microbes Infect. Anti-apoptotic factors of the Bcl-2 protein family (Bcl-2, Bcl-xl) are the most abundantly documented repressors of Beclin 1. Clipboard, Search History, and several other advanced features are temporarily unavailable. Contribution to pathogenesis of accessory proteins of deadly human coronaviruses. Its counterpart in yeast, the Atg1-Atg13-Atg17 complex, is also essential for the regulation of autophagy, and integrates regulation from TOR and diverse signaling pathways [1012]. The goal of this review is to summarize, in brief, what we know so far about the relationship between autophagy and viruses, particularly for those who are not familiar with the field. government site. Shang K, Xiao L, Zhang X, Zang L, Zhao D, Wang C, Wang X, Zhou T, Zhu C, Zhu X. Mol Plant Pathol. doi: 10.1128/jvi.00264-23. U54 AI057156/AI/NIAID NIH HHS/United States, R01AI151267/AI/NIAID NIH HHS/United States, U54AI057156/AI/NIAID NIH HHS/United States. 2016 Sep 12;90(19):8673-85. doi: 10.1128/JVI.00915-16. 2023 Mar;24(3):167-185. doi: 10.1038/s41580-022-00542-2. 2016;95:149-95. doi: 10.1016/bs.aivir.2016.02.002. The mTOR kinase is essential for the control of autophagy by growth factors, insulin, nutrients, calcium signaling, ATP level, hypoxia and oxidative stress [23]. Studies of the cellular autophagy pathway have exploded over the past twenty years. Several viruses are known to inhibit either autophagic signaling, or autophagic maturation, as shown. Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, Heintz N, Yue Z. Autophagy in the control and pathogenesis of viral infection. Autophagy: What is It and 8 Ways to Enhance It - DrJockers.com Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. This study showed that HDAC8 (histone deacetylase 8) inhibits FMDV replication by regulating innate . Leib DA, Alexander DE, Cox D, Yin J, Ferguson TA. The role of autophagy in viral infections Would you like email updates of new search results? HSV-1 ICP34.5, KSHV orf16, and MHV-68 M11 inhibit autophagosome formation by binding to the Beclin 1 autophagy signaling molecule. Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J, Mazure NM. Therefore, it is not unexpected to find that some antiapoptotic proteins also repress autophagy. However, during the late phase of macrophage infection, HSV-1 stimulates autophagosome formation. UPR activation is thought, in turn, to drive the synthesis of LMP1 [85]. Autophagy and viruses: adversaries or allies? Epub 2023 Feb 24. The same host autophagy protein, Beclin 1, is targeted by different herpesviruses and via diverse strategies, which is not surprising given the central role of Beclin 1 in the regulation of autophagy. In order to block autophagy, ICP34.5 is also able to recruit the phosphatase 1 alpha PP1, leading to the dephosphorylation of eIF2. Analysis of the role of autophagy in replication of herpes simplex virus in cell culture. Cell Commun Signal. Roa-Linares VC, Escudero-Flrez M, Vicente-Manzanares M, Gallego-Gmez JC. In view of the interplay known to exist between apoptosis and autophagy [74,75], apoptosis-inhibitory HCMV gene products, such as vMIA, VICA or UL38, could also be involved in the control of autophagy by HCMV [76]. Viruses. Autophagy and Mammalian Viruses: Roles in Immune Response, Viral Tanida I, Tanida-Miyake E, Komatsu M, Ueno T, Kominami E. Human Apg3p/Aut1p homologue is an authentic E2 enzyme for multiple substrates, GATE-16, GABARAP; MAP-LC3; facilitates the conjugation of hApg12p to hApg5p. HCV induces the accumulation of autophagosomes in infected cells, but inhibits their fusion with lysosomes [54], and seems to require autophagy at an early stage of the infection [55]. Bethesda, MD 20894, Web Policies Chaumorcel M, Souquere S, Pierron G, Codogno P, Esclatine A. Ichimura Y, Kirisako T, Takao T, Satomi Y, Shimonishi Y, Ishihara N, Mizushima N, Tanida I, Kominami E, Ohsumi M, Noda T, Ohsumi Y. Indeed, autophagy is induced during the first hours of infection, independently of the expression of viral proteins, because this stimulation is observed even in the context of cells infected with UV-inactivated HCMV (our unpublished data). The .gov means its official. EBV infects the oral epithelium, where it undergoes lytic replication, and resting B lymphocytes, where it establishes long-term latency. The precise mechanisms involved in the inhibition of autophagy by HCMV are still unclear. Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. The regulatory protein FLIP, which contains death effector domains (DED) such as the adaptator protein FADD and the procaspases 8 and 10, regulates apoptosis from death receptors [94]. Destroys pathogens in a cell that can damage it, like viruses and bacteria. Under normal conditions, basal autophagy has a housekeeping function, allowing cells to recycle organelles and long-lived proteins, but autophagy is also induced in response to various forms of stress, such as starvation, depletion of growth factors, low energy levels, hypoxia, oxidative stress, ER stress and pathogen infection. These findings suggest that HHV-6 infection could also modify the level of autophagy. Lee DY, Sugden B. The definition of autophagy is "consumption of the body's own tissue as a metabolic process occurring in starvation and certain diseases." Researchers believe that autophagy is a survival mechanism, or a way that the body cleverly responds to stress in order to protect itself. The https:// ensures that you are connecting to the Autophagy during viral infection a double-edged sword The site is secure. An official website of the United States government. It is apparently used also by cells to eliminate invading pathogens. Talloczy et al. Sir D, Chen WL, Choi J, Wakita T, Yen TS, Ou JH. Zhu H, Wu H, Liu X, Li B, Chen Y, Ren X, Liu CG, Yang JM. Several recent reviews address the interplay between viruses and autophagy [39,42,43]. Cheng G, Brett ME, He B. Val193 and Phe195 of the gamma 1 34.5 protein of herpes simplex virus 1 are required for viral resistance to interferon-alpha/beta. This site needs JavaScript to work properly. Two ubiquitin-like conjugation systems (5) lead to the conjugation of Atg12 to Atg5, and of LC3 to phosphatidylethanolamine (PE). The fact that HCMV-infected cells are resistant to autophagy induced by rapamycin, an mTOR inhibitor, and by lithium chloride, which acts independently of mTOR, also suggests that HCMV targets several regulatory pathways [71]. Epub 2016 Mar 10. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells.
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