Update of the human and mouse SERPINgene superfamily

Heit, Claire; Jackson, Brian E.; McAndrews, Monica; Wright, Mathew W.; Thompson, David C.; Silverman, Gary A.; Nebert, Daniel W.; Vasiliou, Vasilis

doi:10.1186/1479-7364-7-22

Cited by 215 publications

(184 citation statements)

References 78 publications

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“…Aox4 and SerpinA3i . Considering that SERPINA3 inhibits cathepsin G released by activated neutrophils (Heit et al, 2013), one can expect phenotypic immunological inference of SERPINA3 inactivation in the 101 reported 129 ESC-derived genetically modified mouse lines of which the targeted gene flanks the SerpinA3i locus. In an attempt to link the Aox4 passenger mutation to a phenotype observed in genetically modified congenic mice targeting an Aox4 -neighboring gene, we found that mice deficient in phospholipase Cε (PLCε) showed a similar thickening of the epidermis (Martins et al, 2014) as observed in Aox4 null mice (Terao et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice

et al. 2015

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SUMMARY Targeted mutagenesis in mice is a powerful tool for functional analysis of genes. However, genetic variation between embryonic stem cells (ESCs) used for targeting (previously almost exclusively 129-derived) and recipient strains (often C57BL/6J) typically results in congenic mice in which the targeted gene is flanked by ESC-derived passenger DNA potentially containing mutations. Comparative genomic analysis of 129 and C57BL/6J mouse strains revealed indels and single nucleotide polymorphisms resulting in alternative or aberrant amino acid sequences in 1,084 genes in the 129-strain genome. Annotating these passenger mutations to the reported genetically modified congenic mice that were generated using 129-strain ESCs revealed that nearly all these mice possess multiple passenger mutations potentially influencing the phenotypic outcome. We illustrated this phenotypic interference of 129-derived passenger mutations with several case studies and developed a Me-PaMuFind-It web tool to estimate the number and possible effect of passenger mutations in transgenic mice of interest.

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Section: Discussionmentioning

confidence: 99%

Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice

et al. 2015

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“…While this is the first report of a very large number of serpin transcripts from male ticks, data presented here are not unusual. High numbers of serpin sequences were reported in ticks I. scapularis (Mulenga et al, 2009), R. pulchellus (direct submission), and A. maculatum (Karim et al, 2011), in mosquitoes Anopheles gambiae, Culex quinquefasciatus , and Aedes aegypti (Rawlings et al, 2012), in Bombyx mori (Zou et al, 2009), Tribolium (Zou et al, 2007), Drosophila (Reichhart, 2005), in mouse and human genomes (Puente and López-Otín, 2004; Gatto et al, 2013; Heit et al, 2013), and in Arabidopsis and Oryza sativa (Fluhr et al, 2012). Such large serpin counts across a great diversity of taxa indicate the importance of this protein family in regulating homeostasis in most branches of life.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic analyses of male and female Amblyomma americanum tick expressed serine protease inhibitors (serpins)

Porter

Radulović

Kim

et al. 2015

Ticks and Tick-borne Diseases

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Serine protease inhibitors (serpins) are a diverse family of proteins that is conserved across taxa. The diversity of Amblyomma americanum serpins (AAS) is far more complex than previously thought as revealed by discovery of 57 and 33 AAS transcripts that are respectively expressed in male and female A. americanum ticks, with 30 found in both. While distinct reproductively, both male and female metastriate ticks, such as A. americanum, require a blood meal. Thus, 30 AAS sequences found in both male and female ticks could play important role(s) in regulating tick feeding and thus represent attractive candidates for anti-tick vaccine development. Of significant interest, 19 AAS sequences expressed in male and female ticks are also part of the 48 AAS sequences expressed in fed female tick salivary glands or midguts; two organs through which the tick interacts with host blood and immune response factors. Considered the most important domain for serpin function, the reactive center loop (RCL) is further characterized by a single ‘P1’ site amino acid residue, which is central to determining the protease regulated by the serpin. In this study, a diversity of 17 different P1 site amino acid residues were predicted, suggesting that A. americanum serpins potentially regulate a large number of proteolytic pathways. Our data also indicate that some serpins in this study could regulate target protease common to all tick species, in that more than 40% of AAS show 58–97% inter-species amino acid conservation. Of significance, 24% of AAS showed 62–100% inter-species conservation within the functional RCL domain, with 10 RCLs showing ≥90–100% conservation. In vertebrates, serpins with basic residues at the P1 site regulate key host defense pathways, which the tick must evade to feed successfully. Interestingly, we found that AAS sequences with basic or polar uncharged residues at the putative P1 site are more likely to be conserved across tick species. Another notable observation from our data is that AAS sequences found only in female ticks and those found in both males and females, but not those found only in male ticks, were highly conserved in other tick species. While descriptive, this study provides the basis for more in-depth studies exploring the roles of serpins in tick feeding physiology.

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“…We have previously shown that the severity of gluten immunopathology in NOD/DQ8 mice is influenced by the microbiota with which these mice are colonized and that administration of recombinant L. lactis expressing elafin can attenuate the inflammatory response of the host to gluten (12,23,24). Serpins are produced by a wide range of organisms and play a key role in maintaining immune homeostasis (25,26). In the gut, serpins are expressed at mucosal surfaces and are involved in regulating barrier function (27,28).…”

Section: Discussionmentioning

confidence: 99%

A Commensal Bifidobacterium longum Strain Prevents Gluten-Related Immunopathology in Mice through Expression of a Serine Protease Inhibitor

McCarville

Dong

Caminero

et al. 2017

Appl Environ Microbiol

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Microbiota-modulating strategies, including probiotic administration, have been tested for the treatment of chronic gastrointestinal diseases despite limited information regarding their mechanisms of action. We previously demonstrated that patients with active celiac disease have decreased duodenal expression of elafin, a human serine protease inhibitor, and supplementation of elafin by a recombinant Lactococcus lactis strain prevents gliadin-induced immunopathology in the NOD/DQ8 mouse model of gluten sensitivity. The commensal probiotic strain Bifidobacterium longum NCC2705 produces a serine protease inhibitor (Srp) that exhibits immune-modulating properties. Here, we demonstrate that B. longum NCC2705, but not a srp knockout mutant, attenuates gliadin-induced immunopathology and impacts intestinal microbial composition in NOD/DQ8 mice. Our results highlight the beneficial effects of a serine protease inhibitor produced by commensal B. longum strains.IMPORTANCE Probiotic therapies have been widely used to treat gastrointestinal disorders with variable success and poor mechanistic insight. Delivery of specific antiinflammatory molecules has been limited to the use of genetically modified organisms, which has raised some public and regulatory concerns. By examining a specific microbial product naturally expressed by a commensal bacterial strain, we provide insight into a mechanistic basis for the use of B. longum NCC2705 to help treat gluten-related disorders.KEYWORDS probiotic, microbiota, gluten, serpin, celiac, commensal M icrobiota-modulating therapies have been tested for the treatment of chronic gastrointestinal diseases and disorders with inconsistent findings. Probiotics are live microorganisms which, when administered in adequate amounts, confer a health benefit to the host (57). Specific strains have shown modest efficacy in treatment of irritable bowel syndrome (IBS) (1); of complications of inflammatory bowel disease (IBD), such as pouchitis (2); and of celiac disease (CeD), a chronic enteropathy caused by ingestion of gluten-containing cereals in genetically susceptible individuals (3). In particular, a number of strains belonging to the genus Bifidobacterium have been proposed as beneficial supplements for a wide range of health conditions (4). Depletions in bifidobacteria have been noted in patients with CeD (5), and attempts have been made to supplement some strains as a therapy for CeD (3, 6). However, despite great public interest in the clinical use of specific probiotic strains for intestinal

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Update of the human and mouse SERPINgene superfamily

Cited by 215 publications

References 78 publications

Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice

Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice

Bioinformatic analyses of male and female Amblyomma americanum tick expressed serine protease inhibitors (serpins)

A Commensal Bifidobacterium longum Strain Prevents Gluten-Related Immunopathology in Mice through Expression of a Serine Protease Inhibitor

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