The Human Cytomegalovirus UL36 Gene Controls Caspase-Dependent and -Independent Cell Death Programs Activated by Infection of Monocytes Differentiating to Macrophages▿
| Autor: | A. Louise McCormick, Linda Roback, Courtney St. Clair, Devon Livingston-Rosanoff |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Human cytomegalovirus
Programmed cell death Virulence Factors Immunology Cytomegalovirus Apoptosis medicine.disease_cause Microbiology Herpesviridae Monocytes Cell Line Gene Knockout Techniques Viral Proteins Virology medicine Macrophage Humans Caspase biology Monocyte Macrophages medicine.disease Cell biology Virus-Cell Interactions medicine.anatomical_structure Cell culture Insect Science Caspases biology.protein |
| Popis: | The cellular protease caspase-8 activates extrinsic apoptosis and also functions to promote monocyte-to-macrophage differentiation. Differentiation-induced alterations to antiviral caspase-8-dependent cell death pathways are unclear. Here, we show THP-1 monocyte-to-macrophage differentiation alters the specific cell death pathways activated in response to human cytomegalovirus (HCMV) infection. Employing viruses with mutations in UL36, the gene that encodes theviralinhibitor ofcaspase-8activation (vICA), our data indicate that both caspase-dependent and -independent death pathways are activated in response to infection. Activation of caspase-dependent and -independent cell death responses restricted growth of vICA-deficient viruses, and vICA/pUL36 inhibited either response. Thus, these studies also reveal that the UL36 gene controls a caspase-independent cell death pathway. The impact of caspases on control of antiviral responses differed at early and late stages of macrophage differentiation. Early in differentiation, vICA-deficient virus-induced cell death was dependent on caspases and inhibited by the pan-caspase inhibitor z-VAD(OMe)-fluoromethyl ketone. In contrast, virus-induced death at late times of differentiation was caspase independent. Additional unlabeled and fluorescent inhibitors indicated that caspase-8 promoted death from within infected cells at early but not late stages of differentiation. These data highlight the multifunctional role of vICA/pUL36 as HCMV encounters various antiviral responses during macrophage differentiation. |
| Databáze: | OpenAIRE |
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