scholarly journals Species-Specific Inhibition of Necroptosis by HCMV UL36

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2134
Author(s):  
Elena Muscolino ◽  
Claudia Castiglioni ◽  
Renke Brixel ◽  
Giada Frascaroli ◽  
Wolfram Brune
Keyword(s):  
Cell Death ◽  
Death Receptor ◽  
Kinase Domain ◽  
Virus Species ◽  
Molluscum Contagiosum Virus ◽  
Narrow Host Range ◽  
Cell Death Pathway ◽  
Species Specific ◽  
Simplex Virus

Viral infection activates cellular antiviral defenses including programmed cell death (PCD). Many viruses, particularly those of the Herpesviridae family, encode cell death inhibitors that antagonize different forms of PCD. While some viral inhibitors are broadly active in cells of different species, others have species-specific functions, probably reflecting the co-evolution of the herpesviruses with their respective hosts. Human cytomegalovirus (HCMV) protein UL36 is a dual cell death pathway inhibitor. It blocks death receptor-dependent apoptosis by inhibiting caspase-8 activation, and necroptosis by binding to the mixed lineage kinase domain-like (MLKL) protein and inducing its degradation. While UL36 has been shown to inhibit apoptosis in human and murine cells, the specificity of its necroptosis-inhibiting function has not been investigated. Here we show that UL36 interacts with both human and murine MLKL, but has a higher affinity for human MLKL. When expressed by a recombinant mouse cytomegalovirus (MCMV), UL36 caused a modest reduction of murine MLKL levels but did not inhibit necroptosis in murine cells. These data suggest that UL36 inhibits necroptosis, but not apoptosis, in a species-specific manner, similar to ICP6 of herpes simplex virus type 1 and MC159 of molluscum contagiosum virus. Species-specific necroptosis inhibition might contribute to the narrow host range of these viruses.

scholarly journals Herpes Simplex Virus Type 1-induced FasL Expression in Human Monocytic Cells and Its Implications for Cell Death, Viral Replication, and Immune Evasion

2011 ◽  
Vol 24 (1) ◽  
pp. 11-26 ◽  
Author(s):  
Alexandre Iannello ◽  
Olfa Debbeche ◽  
Raoudha El Arabi ◽  
Suzanne Samarani ◽  
David Hamel ◽  
...  
Keyword(s):  
Cell Death ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Immune Evasion ◽  
Herpes Simplex Virus Type ◽  
Fasl Expression ◽  
Monocytic Cells ◽  
Simplex Virus

scholarly journals Epilepsy and Apoptosis Pathways

2005 ◽  
Vol 25 (12) ◽  
pp. 1557-1572 ◽  
Author(s):  
David C Henshall ◽  
Roger P Simon
Keyword(s):  
Cell Death ◽  
Neuronal Death ◽  
Apoptotic Cell ◽  
Death Receptor ◽  
Apoptotic Pathway ◽  
Apoptosis Pathway ◽  
Cell Death Pathway ◽  
Pathway Function ◽  
Apoptosis Pathways ◽  
Molecular Machinery

Epilepsy is a common, chronic neurologic disorder characterized by recurrent unprovoked seizures. Experimental modeling and clinical neuroimaging of patients has shown that certain seizures are capable of causing neuronal death. Such brain injury may contribute to epileptogenesis, impairments in cognitive function or the epilepsy phenotype. Research into cell death after seizures has identified the induction of the molecular machinery of apoptosis. Here, the authors review the clinical and experimental evidence for apoptotic cell death pathway function in the wake of seizure activity. We summarize work showing intrinsic (mitochondrial) and extrinsic (death receptor) apoptotic pathway function after seizures, activation of the caspase and Bcl-2 families of cell death modulators and the acute and chronic neuropathologic impact of intervening in these molecular cascades. Finally, we describe evolving data on nonlethal roles for these proteins in neuronal restructuring and cell excitability that have implications for shaping the epilepsy phenotype. This review highlights the work to date on apoptosis pathway signaling during seizure-induced neuronal death and epileptogenesis, and speculates on how emerging roles in brain remodeling and excitability have enriched the number of therapeutic strategies for protection against seizure-damage and epileptogenesis.

Location, location, location: A compartmentalized view of TNF-induced necroptotic signaling

2021 ◽  
Vol 14 (668) ◽  
pp. eabc6178
Author(s):  
André L. Samson ◽  
Sarah E. Garnish ◽  
Joanne M. Hildebrand ◽  
James M. Murphy
Keyword(s):  
Cell Death ◽  
Protein Kinases ◽  
Host Defense ◽  
Kinase Domain ◽  
Dependent Manner ◽  
Cell Type ◽  
Mixed Lineage Kinase ◽  
Cell Death Pathway ◽  
Subcellular Compartmentalization ◽  
High Degree

Necroptosis is a lytic, proinflammatory cell death pathway, which has been implicated in host defense and, when dysregulated, the pathology of many human diseases. The central mediators of this pathway are the receptor-interacting serine/threonine protein kinases RIPK1 and RIPK3 and the terminal executioner, the pseudokinase mixed lineage kinase domain–like (MLKL). Here, we review the chronology of signaling along the RIPK1-RIPK3-MLKL axis and highlight how the subcellular compartmentalization of signaling events controls the initiation and execution of necroptosis. We propose that a network of modulators surrounds the necroptotic signaling core and that this network, rather than acting universally, tunes necroptosis in a context-, cell type–, and species-dependent manner. Such a high degree of mechanistic flexibility is likely an important property that helps necroptosis operate as a robust, emergency form of cell death.

scholarly journals Pseudorabies Virus EP0 Protein Counteracts an Interferon-Induced Antiviral State in a Species-Specific Manner

2006 ◽  
Vol 80 (21) ◽  
pp. 10871-10873 ◽  
Author(s):  
Alla Brukman ◽  
L. W. Enquist
Keyword(s):  
Pseudorabies Virus ◽  
Host Cells ◽  
Broad Host Range ◽  
Primary Cells ◽  
Varicella Zoster ◽  
Specific Manner ◽  
Natural Hosts ◽  
Species Specific ◽  
Simplex Virus

ABSTRACT Pseudorabies virus (PRV), an alphaherpesvirus related to herpes simplex virus type 1 and varicella-zoster virus, infects a broad host range of mammals. A striking characteristic of PRV infection is the different symptoms and outcomes of infection in natural and nonnatural hosts. Adult pigs, the natural hosts of PRV, survive infection with only mild respiratory symptoms, while nonnatural hosts, including rodents and cattle, invariably die after exhibiting neurological symptoms. Here, we show that the PRV EP0 protein is necessary to overcome an interferon-mediated antiviral response in primary cells from the natural host of PRV but is not necessary in nonnatural-host cells.

scholarly journals RIPK3 Facilitates Host Resistance to Oral Toxoplasma gondii Infection

2021 ◽  
Vol 89 (5) ◽  
Author(s):  
Patrick W. Cervantes ◽  
Bruno Martorelli Di Genova ◽  
Billy Joel Erazo Flores ◽  
Laura J. Knoll
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Parasite Burden ◽  
Kinase Domain ◽  
Content Type ◽  
Protection Mechanism ◽  
Cell Death Pathway ◽  
Toxoplasma Gondii Infection

ABSTRACT Toxoplasma gondii infection activates pattern recognition receptor (PRR) pathways that drive innate inflammatory responses to control infection. Necroptosis is a proinflammatory cell death pathway apart from the innate immune response that has evolved to control pathogenic infection. In this study, we further defined the role of Z-DNA binding protein 1 (ZBP1) as a PRR and assessed its contribution to necroptosis as a host protection mechanism to T. gondii infection. We found that ZBP1 does not induce proinflammatory necroptosis cell death, and ZBP1 null mice have reduced survival after oral T. gondii infection. In contrast, mice deleted in receptor-interacting serine/threonine-protein kinase 3 (RIPK3−/−), a central mediator of necroptosis, have significantly improved survival after oral T. gondii infection without a reduction in parasite burden. The physiological consequences of RIPK3 activity did not show any differences in intestine villus immunopathology, but RIPK3−/− mice showed higher immune cell infiltration and edema in the lamina propria. The contribution of necroptosis to host survival was clarified with mixed-lineage kinase domain-like pseudokinase null (MLKL−/−) mice. We found MLKL−/− mice succumbed to oral T. gondii infection the same as wild-type mice, indicating necroptosis-independent RIPK3 activity impacts host survival. These results provide new insights on the impacts of proinflammatory cell death pathways as a mechanism of host defense to oral T. gondii infection.

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