The Human Cytomegalovirus Protein TRS1 Inhibits Autophagy via Its Interaction with Beclin 1

Chaumorcel, Magali; Lussignol, Marion; Mouna, Lina; Cavignac, Yolaine; Fahie, Kamau; Cotte‐Laffitte, Jacqueline; Geballe, Adam P.; Brune, Wolfram; Beau, Isabelle; Codogno, Patrice; Esclatine, Audrey

doi:10.1128/jvi.05746-11

Cited by 151 publications

(152 citation statements)

References 65 publications

Supporting

Mentioning

143

Contrasting

Order By: Relevance

“…HCMV infection increased the levels of LC3B-II at 24 hpi, but these levels dropped at 72 hpi such that they were only slightly higher in the infected cells. This is consistent with prior work showing that HCMV transiently induces autophagy early in the infection (26)(27)(28). Incubation of cells with 100 mM trehalose from the beginning of the infection further increased LC3B-II levels in both the mock-infected and HCMVinfected cells at 24 and 72 hpi, with a greater increase observed in the infected cells.…”

Section: Trehalose Induces Autophagosome Formation In Infected Hffssupporting

confidence: 80%

“…In fact, it appears that activation of autophagy occurs very early during HCMV infection of fibroblasts and does not require de novo protein synthesis since UV-irradiated virus induces autophagy (26). This induction appears to be transient, and at later times in the infection it has been reported that autophagy may be downregulated through the interaction of the viral gene product TRS1 with beclin-1 (27,28).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types

Belzile

Sabalza

Craig

et al. 2016

J Virol

View full text Add to dashboard Cite

Human cytomegalovirus (HCMV) is the major viral cause of birth defects and a serious problem in immunocompromised individuals and has been associated with atherosclerosis. Previous studies have shown that the induction of autophagy can inhibit the replication of several different types of DNA and RNA viruses. The goal of the work presented here was to determine whether constitutive activation of autophagy would also block replication of HCMV. Most prior studies have used agents that induce autophagy via inhibition of the mTOR pathway. However, since HCMV infection alters the sensitivity of mTOR kinase-containing complexes to inhibitors, we sought an alternative method of inducing autophagy. We chose to use trehalose, a nontoxic naturally occurring disaccharide that is found in plants, insects, microorganisms, and invertebrates but not in mammals and that induces autophagy by an mTOR-independent mechanism. Given the many different cell targets of HCMV, we proceeded to determine whether trehalose would inhibit HCMV infection in human fibroblasts, aortic artery endothelial cells, and neural cells derived from human embryonic stem cells. We found that in all of these cell types, trehalose induces autophagy and inhibits HCMV gene expression and production of cell-free virus. Treatment of HCMV-infected neural cells with trehalose also inhibited production of cell-associated virus and partially blocked the reduction in neurite growth and cytomegaly. These results suggest that activation of autophagy by the natural sugar trehalose or other safe mTOR-independent agents might provide a novel therapeutic approach for treating HCMV disease. IMPORTANCEHCMV infects multiple cell types in vivo, establishes lifelong persistence in the host, and can cause serious health problems for fetuses and immunocompromised individuals. HCMV, like all other persistent pathogens, has to finely tune its interplay with the host cellular machinery to replicate efficiently and evade detection by the immune system. In this study, we investigated whether modulation of autophagy, a host pathway necessary for the recycling of nutrients and removal of protein aggregates, misfolded proteins, and pathogens, could be used to target HCMV. We found that autophagy could be significantly increased by treatment with the nontoxic, natural disaccharide trehalose. Importantly, trehalose had a profound inhibitory effect on viral gene expression and strongly impaired viral spread. These data constitute a proof-of-concept for the use of natural products targeting host pathways rather than the virus itself, thus reducing the risk of the development of resistance to treatment. H uman cytomegalovirus (HCMV) infects multiple cell types, including endothelial, smooth muscle, epithelial, and fibroblast cells, monocytes/macrophages, bone marrow progenitor cells, and cells of the neural lineage, and establishes lifelong persistence in the host (for a review, see reference 1). Seroprevalence is high in the general population, and in most healthy individuals, the in...

show abstract

Section: Trehalose Induces Autophagosome Formation In Infected Hffssupporting

confidence: 80%

mentioning

confidence: 99%

Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types

Belzile

Sabalza

Craig

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…1A) and the work of others (31) suggest that PHT cells are resistant to CMV infection, and studies of CMV-infected placentas suggest that CMV specifically targets invasive and endovascular cytotrophoblasts as a means of entry into the fetal compartment (31)(32)(33). CMV is known to inhibit host autophagosome biogenesis during its infection, even when autophagy is stimulated (34,35). However, the specific mechanism(s) underlying the up-regulation of CMV infection by C19MC miRNAs are likely complex, involving diverse viral and/or cellular strategies.…”

Section: Discussionmentioning

confidence: 99%

Human placental trophoblasts confer viral resistance to recipient cells

Delorme-Axford

Donker

Mouillet

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

430

420

View full text Add to dashboard Cite

Placental trophoblasts form the interface between the fetal and maternal environments and serve to limit the maternal-fetal spread of viruses. Here we show that cultured primary human placental trophoblasts are highly resistant to infection by a number of viruses and, importantly, confer this resistance to nonplacental recipient cells by exosome-mediated delivery of specific microRNAs (miRNAs). We show that miRNA members of the chromosome 19 miRNA cluster, which are almost exclusively expressed in the human placenta, are packaged within trophoblast-derived exosomes and attenuate viral replication in recipient cells by the induction of autophagy. Together, our findings identify an unprecedented paracrine and/or systemic function of placental trophoblasts that uses exosome-mediated transfer of a unique set of placental-specific effector miRNAs to directly communicate with placental or maternal target cells and regulate their immunity to viral infections.C19MC | primary human trophoblasts | miR-517-3p

show abstract

“…However, at later times of infection, coinciding with AC formation, HCMV blocks autophagy (Chaumorcel et al 2008) by a mechanism that requires de novo viral protein expression. One viral protein synthesized during this period is TRS1, which has been shown to block autophagosome biogenesis (Chaumorcel et al 2012). Interestingly, TRS1 has been shown to be present in the AC (Buchkovich et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Dynein mediates the localization and activation of mTOR in normal and human cytomegalovirus-infected cells

Clippinger

Alwine

2012

Genes Dev.

View full text Add to dashboard Cite

Activation of stress signaling pathways normally leads to inhibition of the mammalian target of rapamycin complex 1 (mTORC1); however, human cytomegalovirus (HCMV) infection maintains mTORC1 activity in the presence of numerous types of stress. We previously demonstrated that HCMV infection maintains mTORC1 activity during amino acid deprivation through a Ras-related GTP-binding (Rag) protein-independent mechanism. This depends on the colocalization of mTOR and its activator, Rheb (Ras homology enriched in brain)-GTP, to a perinuclear position that corresponds to the viral cytoplasmic assembly compartment (AC). The data presented here show that the HCMV-induced, amino acid depletion-resistant perinuclear localization and activation of mTORC1 occurs as early as 8 h post-infection, prior to AC formation. We show that the molecular motor dynein is required for perinuclear localization of mTORC1 in both uninfected and HCMV-infected cells. Association between dynein and mTOR is shown by coimmunoprecipitation, and inhibition of dynein function using RNAi or the small molecule inhibitor ciliobrevin A inhibits mTORC1 activity in both uninfected and HCMV-infected cells. The data suggest that mTORC1 activation requires dynein-dependent transport to a position in the cell where it can be activated. Thus, the HCMV commandeers a cellular dynein-dependent mTORC1 activation mechanism to maintain stress-resistant mTORC1 activity during infection and to form the AC.

show abstract

The Human Cytomegalovirus Protein TRS1 Inhibits Autophagy via Its Interaction with Beclin 1

Cited by 151 publications

References 65 publications

Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types

Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types

Human placental trophoblasts confer viral resistance to recipient cells

Dynein mediates the localization and activation of mTOR in normal and human cytomegalovirus-infected cells

Contact Info

Product

Resources

About