Vaccinia virus serpin B13R (SPI-2) inhibits interleukin-1beta-converting enzyme and protects virus-infected cells from TNF- and Fas-mediated apoptosis, but does not prevent IL-1beta-induced fever.

Kettle, Susan; Alcamı́, Antonio; Khanna, Anu; Ehret, Robert; Jassoy, Christian; Smith, Geoffrey L.

doi:10.1099/0022-1317-78-3-677

Cited by 193 publications

(132 citation statements)

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“…Infectious organisms have evolved methods for evading the host defense system (30,31). For example, the viral serpin, crmA, prevents the proteolytic activation of interleukin-␤ and protects virus-infected cells from Fas-and tumor necrosis factor-induced apoptosis (32). Similarly, a serpin from the parasitic nematode Brugia malayi, Bm-SPN-2, has been shown to neutralize the activities of human neutrophil-derived proteinases, catG and elastase, and may allow the parasite to escape destruction by the human immune system (33).…”

Section: Discussionmentioning

confidence: 99%

SRP-2 Is a Cross-class Inhibitor That Participates in Postembryonic Development of the Nematode Caenorhabditis elegans

Pak

Kumar

Tsu

et al. 2004

Journal of Biological Chemistry

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High molecular weight serpins are members of a large superfamily of structurally conserved proteins that inactivate target proteinases by a suicide substrate-like mechanism. In vertebrates, different clades of serpins distribute predominantly to either the intracellular or extracellular space. Although much is known about the function, structure, and inhibitory mechanism of circulating serpins such as ␣ 1 -antitrypsin (SERPINA1) and antithrombin III (SERPINC1), relatively little is known about the function of the vertebrate intracellular (clade B) serpins. To gain a better understanding of the biology of the intracellular serpins, we initiated a comparative genomics study using Caenorhabditis elegans as a model system. A screen of the C. elegans genomic and cDNA databases revealed nine serpin genes, tandemly arrayed on chromosome V. Although the C. elegans serpins represent a unique clade (L), they share significant functional homology with members of the clade B group of intracellular serpins, since they lack typical N-terminal signal peptides and reside intracellularly. To determine whether nematode serpins function as proteinase inhibitors, one family member, srp-2, was chosen for further characterization. Biochemical analysis of recombinant SRP-2 protein revealed SRP-2 to be a dual cross-class inhibitor of the apoptosis-related serine proteinase, granzyme B, and the lysosomal cysteine proteinases, cathepsins K, L, S, and V. Analysis of temporal and spatial expression indicated that SRP-2 was present during early embryonic development and highly expressed in the intestine and hypoderm of larval and adult worms. Transgenic animals engineered to overexpress SRP-2 were slow growing and/or arrested at the first, second, or third larval stages. These data suggest that perturbations of serpin-proteinase balance are critical for correct postembryonic development in C. elegans.Serpins are a unique class of proteinase inhibitors that irreversibly neutralize target proteinases by a mechanism involving the conformational distortion of the proteinase. Serpins have been identified in animals, plants, insects, and certain viruses (1, 2). More recently, serpins have been detected in prokaryotes (3). A search of genome data bases provides evidence for Ͼ500 serpins that are grouped into 17 clades (plus Ͼ10 unclassified orphans) based upon phylogenetic relationships (4). In humans, ϳ35 serpins have been identified. These serpins are distributed among nine clades (A-I), and most are secreted and function in the circulation or extracellular spaces. These serpins regulate proteinases involved in blood coagulation, fibrinolysis, complement activation, inflammation, and extracellular matrix remodeling. In contrast, serpins belonging to clade B reside predominantly intracellularly and have been implicated in regulating apoptosis, tumor progression, and metastasis (5). However, their biological functions in terms of an intact organism have not been well defined. To date, no naturally occurring mutations with an identifiable phenotype...

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Section: Discussionmentioning

confidence: 99%

SRP-2 Is a Cross-class Inhibitor That Participates in Postembryonic Development of the Nematode Caenorhabditis elegans

Pak

Kumar

Tsu

et al. 2004

Journal of Biological Chemistry

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“…Data regarding such viral mechanisms have been accumulating, with reports that viruses such as VACV, myxoma virus, and cowpox viruses encode viral proteins with serpin activity that acts on IL1b-converting enzyme [144][145][146]. Viral proteins, CrmA, B13R, and Serp2, have been shown to have inhibitory effects on the activity of caspase-1, leading to the inhibition of the processing of IL-1b [144][145][146]. Another viral protein involved in this mechanism of immune evasion is the NS1 protein of influenza virus.…”

Section: Inhibition Of Caspase-1mentioning

confidence: 99%

Inflammasomes and its importance in viral infections

León-Juárez²,

et al. 2016

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A complex interplay between pathogen and host determines the immune response during viral infection. A set of cytosolic sensors are expressed by immune cells to detect viral infection. NOD-like receptors (NLRs) comprise a large family of intracellular pattern recognition receptors. Members of the NLR family assemble into large multiprotein complexes, termed inflammasomes, which induce downstream immune responses to specific pathogens, environmental stimuli, and host cell damage. Inflammasomes are composed of cytoplasmic sensor molecules such as NLRP3 or absent in melanoma 2 (AIM2), the adaptor protein ASC (apoptosis-associated speck-like protein containing caspase recruitment domain), and the effector protein procaspase-1. The inflammasome operates as a platform for caspase-1 activation, resulting in caspase-1-dependent proteolytic maturation and secretion of interleukin (IL)-1b and IL-18. This, in turn, activates the expression of other immune genes and facilitates lymphocyte recruitment to the site of primary infection, thereby controlling invading pathogens. Moreover, inflammasomes counter viral replication and remove infected immune cells through an inflammatory cell death, program termed as pyroptosis. As a countermeasure, viral pathogens have evolved virulence factors to antagonise inflammasome pathways. In this review, we discuss the role of inflammasomes in sensing viral infection as well as the evasion strategies that viruses have developed to evade inflammasome-dependent immune responses. This information summarises our understanding of host defence mechanisms against viruses and highlights research areas that can provide new approaches to interfere in the pathogenesis of viral diseases.

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“…Vaccinia virus B13R and B22R gene products show amino acid similarity to serine protease inhibitors (Smith et al, 1989). B13R can block apoptosis induced by Fas and TNF-a (Kettle et al, 1997). Caspase-1 (interleukin-1b-converting enzyme), and presumably other caspases, has been shown to be inhibited by B13R protein.…”

Section: Viral Genes As Caspase Inhibitorsmentioning

confidence: 99%