Adenoviral inhibitors of apoptotic cell death

McNees, Adrienne L.; Gooding, Linda R.

doi:10.1016/s0168-1702(02)00122-3

Cited by 32 publications

(30 citation statements)

References 133 publications

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“…75,76 Viruses can modulate this balance. In the adenovirus system, for example, it has been shown that the existence of several virus-encoded proteins that block TNF-induced apoptosis [77][78][79] may be necessitated by the actions of the adenovirus E1A protein, which sensitizes cells to TNF, likely as a 'side effect' of its other biological activities. 58,80,81 In the experiments reported here, we were unable to observe significant cell death in response to TNF in the absence of cycloheximide in any of the cells tested (control cells, cells expressing high levels of E6 and cells expressing low levels of E6) (data not shown).…”

Section: Discussionmentioning

confidence: 99%

The human papillomavirus 16 E6 protein can either protect or further sensitize cells to TNF: effect of dose

et al. 2005

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High-risk strains of human papillomavirus, including HPV 16, cause human cervical carcinomas, due in part to the activity of their E6 oncogene. E6 interacts with a number of cellular proteins involved in host-initiated apoptotic responses. Paradoxically, literature reports show that E6 can both protect cells from and sensitize cells to tumor necrosis factor (TNF). To examine this apparent contradiction, E6 was transfected into U2OS cells and stable clones were treated with TNF. Intriguingly, clones with a high level of E6 expression displayed an increased sensitivity to TNF by undergoing apoptosis, while those with low expression were resistant. Furthermore, TNF treatment of cells in which the expression of E6 was regulated by the addition of doxycycline demonstrated clearly that while low levels of E6 protect cells from TNF, high levels sensitize cells. Together, these results demonstrate that virus-host interactions can be complex and that both quantitative and qualitative aspects are important in determining outcome.

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Section: Discussionmentioning

confidence: 99%

The human papillomavirus 16 E6 protein can either protect or further sensitize cells to TNF: effect of dose

et al. 2005

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“…This suggests that E3 proteins have an important function in vivo. Indeed, over the past 2 decades, experiments both in cell culture and animal models clearly demonstrated that most E3 proteins have the capacity to modulate immune response mechanisms (5,(7)(8)(9)(10)(11)(12)(13), ranging from inhibition of Ag presentation (14), suppression of NK cell activation (15), downregulation of apoptosis receptors (7)(8)(9)16), and interference with TNF receptor-induced activities (10,17,18).…”

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confidence: 99%

Conserved Amino Acids within the Adenovirus 2 E3/19K Protein Differentially Affect Downregulation of MHC Class I and MICA/B Proteins

Sester

Koebernick

Owen

et al. 2009

The Journal of Immunology

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Successful establishment and persistence of adenovirus (Ad) infections are facilitated by immunosubversive functions encoded in the early transcription unit 3 (E3). The E3/19K protein has a dual role, preventing cell surface transport of MHC class I/HLA class I (MHC-I/HLA-I) Ags and the MHC-I–like molecules (MHC-I chain-related chain A and B [MICA/B]), thereby inhibiting both recognition by CD8 T cells and NK cells. Although some crucial functional elements in E3/19K have been identified, a systematic analysis of the functional importance of individual amino acids is missing. We now have substituted alanine for each of 21 aas in the luminal domain of Ad2 E3/19K conserved among Ads and investigated the effects on HLA-I downregulation by coimmunoprecipitation, pulse-chase analysis, and/or flow cytometry. Potential structural alterations were monitored using conformation-dependent E3/19K-specific mAbs. The results revealed that only a small number of mutations abrogated HLA-I complex formation (e.g., substitutions W52, M87, and W96). Mutants M87 and W96 were particularly interesting as they exhibited only minimal structural changes suggesting that these amino acids make direct contacts with HLA-I. The considerable number of substitutions with little functional defects implied that E3/19K may have additional cellular target molecules. Indeed, when assessing MICA/B cell-surface expression we found that mutation of T14 and M82 selectively compromised MICA/B downregulation with essentially no effect on HLA-I modulation. In general, downregulation of HLA-I was more severely affected than that of MICA/B; for example, substitutions W52, M87, and W96 essentially abrogated HLA-I modulation while largely retaining the ability to sequester MICA/B. Thus, distinct conserved amino acids seem preferentially important for a particular functional activity of E3/19K.

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“…However, subsequent reports demonstrated that efficient down-regulation depends on both proteins (12,13,20). Taken together, the 10.4 -14.5 complex, also named receptor internalization and degradation (RID), modulates a selective set of plasma membrane receptors involved in apoptosis and growth control (13,22,23). The molecular basis for the exquisite target specificity of 10.4 -14.5 remains unknown.…”

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confidence: 99%

Two Distinct Transport Motifs in the Adenovirus E3/10.4-14.5 Proteins Act in Concert to Down-modulate Apoptosis Receptors and the Epidermal Growth Factor Receptor

Hilgendorf

Lindberg

Ruzsics

et al. 2003

Journal of Biological Chemistry

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Adenoviral inhibitors of apoptotic cell death

Cited by 32 publications

References 133 publications

The human papillomavirus 16 E6 protein can either protect or further sensitize cells to TNF: effect of dose

The human papillomavirus 16 E6 protein can either protect or further sensitize cells to TNF: effect of dose

Conserved Amino Acids within the Adenovirus 2 E3/19K Protein Differentially Affect Downregulation of MHC Class I and MICA/B Proteins

Two Distinct Transport Motifs in the Adenovirus E3/10.4-14.5 Proteins Act in Concert to Down-modulate Apoptosis Receptors and the Epidermal Growth Factor Receptor

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