2017
DOI: 10.1128/jvi.00393-17
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Cbl E3 Ligase Mediates the Removal of Nectin-1 from the Surface of Herpes Simplex Virus 1-Infected Cells

Abstract: The Cbl E3 ligase has been linked to the down-modulation of surface signaling responses by inducing internalization of surface receptors. The adaptor protein CIN85 is a partner of Cbl that augments many of these interactions. Previously, an interaction was demonstrated between ICP0 and CIN85, which results in the removal of epidermal growth factor receptor (EGFR) from the surface of the infected cells with a concomitant attenuation of EGFR signaling. Here, we examined whether Cbl mediates the removal of the he… Show more

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Cited by 21 publications
(22 citation statements)
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“…The multifunctional HSV-1 immediate early protein ICP0 antagonizes EGFR and PI3K-Akt signaling through an interaction with CIN85 (90). Further, it was recently shown that interaction between CIN85 and ICP0 recruits Cbl to downregulate Nectin-1 at the surface of infected cells and prevents superinfection (91). Because EGFR/PI3K signaling promotes the establishment of latency and because its attenuation enhances reactivation, we postulate that UL135mediated control of EGFR is to primarily regulate exit from latency.…”
Section: Discussionmentioning
confidence: 83%
“…The multifunctional HSV-1 immediate early protein ICP0 antagonizes EGFR and PI3K-Akt signaling through an interaction with CIN85 (90). Further, it was recently shown that interaction between CIN85 and ICP0 recruits Cbl to downregulate Nectin-1 at the surface of infected cells and prevents superinfection (91). Because EGFR/PI3K signaling promotes the establishment of latency and because its attenuation enhances reactivation, we postulate that UL135mediated control of EGFR is to primarily regulate exit from latency.…”
Section: Discussionmentioning
confidence: 83%
“…The decreased uptake could be due to cell surface alterations that occur during infection. Consistent with this hypothesis, we have previously reported that infected cells are not susceptible to secondary HSV-1 infections, and this occurs because of removal of the viral entry receptor Nectin-1 from the surface of the infected cells via the ICP0/Cbl/CIN85 endocytic complex (34). The mechanisms by which EVs enter the cells or are targeted to selected cell types are poorly understood, but they appear to involve different types of endocytosis.…”
Section: Figmentioning
confidence: 60%
“…Thus, HEL cells were exposed to either HSV-1(F) or various mutant viruses at 1 PFU/cell, and the intracellular levels of CD63 were assessed at 24 h postinfection by immunoblot analysis. The mutant viruses used in this experiment included a ΔICP27 virus, in which post-alpha gene expression does not occur (30); a Δ⌱CP0 virus, which is a transactivation-deficient mutant that also fails to block innate immune responses (31-33); a Ring Finger (RF) mutant of ICP0 which fails to ubiquitinate host targets (31-33); a virus which carries a single amino acid substitution (D199A) in ICP0 that results in its nuclear retention and therefore failure to execute its cytoplasmic functions (34,35); a ΔVHS virus, which does not encode the viral RNase VHS (36); a Δ␥1 34.5 virus, which cannot block host translational shutoff and autophagy (37,38); and a ΔUL46 virus, which fails to combat antiviral responses (39). The cells were harvested at 24 h postinfection, and the amount of intracellular CD63 was assessed by immunoblot analysis.…”
Section: Resultsmentioning
confidence: 99%
“…Also, receptor nectin-1 resides in cell junctions, where the virus can bind (via gD) to gain entry into adjacent cells [ 51 ]. However, because HSV-1 downregulates nectin-1 in infected cells, this receptor is only present on the adjoining uninfected cell [ 52 ]. Consequently, virions released into lateral junctions (as opposed to viral proteins on the plasma membrane) are unlikely to be the drivers of fusion for Syn mutants or in salubrinal treatments because they cannot fuse with the cell from which they emerged [ 52 ].…”
Section: Discussionmentioning
confidence: 99%