scholarly journals A triple threat: the Parastagonospora nodorum SnTox267 effector exploits three distinct host genetic factors to cause disease in wheat

2021 ◽  
Author(s):  
Jonathan K Richards ◽  
Gayan Kariyawasam, Gayan ◽  
Sudeshi Seneviratne ◽  
Nathan A Wyatt ◽  
Steven S Xu ◽  
...  
Keyword(s):  
Cell Death ◽  
Fungal Pathogen ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Effector Proteins ◽  
Protein Isoforms ◽  
Host Susceptibility ◽  
Local Selection ◽  
Parastagonospora Nodorum ◽  
Host Pathways

Parastagonospora nodorum is a fungal pathogen of wheat. As a necrotrophic specialist, it deploys a suite of effector proteins that target dominant host susceptibility genes to elicit programmed cell death (PCD). Nine effector-host susceptibility gene interactions have been reported in this pathosystem, presumed to be governed by unique pathogen effectors. This study presents the characterization of the SnTox267 necrotrophic effector that hijacks two separate host pathways to cause necrosis. An association mapping approach identified SnTox267 and the generation of gene-disrupted mutants and gain-of-function transformants confirmed its role in Snn2-, Snn6-, and Snn7-mediated necrosis. The Snn2 and Snn6 host susceptibility genes were complementary, and together they functioned cooperatively to elicit SnTox267-induced necrosis in the same light-dependent PCD pathway. Additionally, we showed that SnTox267 targeted Snn7, resulting in light-independent necrosis. Therefore, SnTox267 co-opts two distinct host pathways to elicit PCD. SnTox267 sequence comparison among a natural population of 197 North American P. nodorum isolates revealed 20 protein isoforms conferring variable levels of virulence, indicating continuing selection pressure on this gene. Protein isoform prevalence among discrete populations indicated that SnTox267 has likely evolved in response to local selection pressures and has diversified more rapidly in the Upper Midwest. Deletion of SnTox267 resulted in the upregulation of the unrelated effector genes SnToxA, SnTox1, and SnTox3, providing evidence for a complex genetic compensation mechanism. These results illustrate a novel evolutionary path by which a necrotrophic fungal pathogen uses a single proteinaceous effector to hijack two host pathways to induce cell death.  

scholarly journals The Novel ALG-2 Target Protein CDIP1 Promotes Cell Death by Interacting with ESCRT-I and VAPA/B

2021 ◽  
Vol 22 (3) ◽  
pp. 1175
Author(s):  
Ryuta Inukai ◽  
Kanako Mori ◽  
Keiko Kuwata ◽  
Chihiro Suzuki ◽  
Masatoshi Maki ◽  
...  
Keyword(s):  
Cell Death ◽  
Essential Gene ◽  
Susceptibility Gene ◽  
Target Protein ◽  
Hek293 Cells ◽  
Dependent Manner ◽  
Gene Encoding ◽  
Endosomal Sorting ◽  
Cell Death Pathways ◽  
Apoptotic Protein

Apoptosis-linked gene 2 (ALG-2, also known as PDCD6) is a member of the penta-EF-hand (PEF) family of Ca2+-binding proteins. The murine gene encoding ALG-2 was originally reported to be an essential gene for apoptosis. However, the role of ALG-2 in cell death pathways has remained elusive. In the present study, we found that cell death-inducing p53 target protein 1 (CDIP1), a pro-apoptotic protein, interacts with ALG-2 in a Ca2+-dependent manner. Co-immunoprecipitation analysis of GFP-fused CDIP1 (GFP-CDIP1) revealed that GFP-CDIP1 associates with tumor susceptibility gene 101 (TSG101), a known target of ALG-2 and a subunit of endosomal sorting complex required for transport-I (ESCRT-I). ESCRT-I is a heterotetrameric complex composed of TSG101, VPS28, VPS37 and MVB12/UBAP1. Of diverse ESCRT-I species originating from four VPS37 isoforms (A, B, C, and D), CDIP1 preferentially associates with ESCRT-I containing VPS37B or VPS37C in part through the adaptor function of ALG-2. Overexpression of GFP-CDIP1 in HEK293 cells caused caspase-3/7-mediated cell death. In addition, the cell death was enhanced by co-expression of ALG-2 and ESCRT-I, indicating that ALG-2 likely promotes CDIP1-induced cell death by promoting the association between CDIP1 and ESCRT-I. We also found that CDIP1 binds to vesicle-associated membrane protein-associated protein (VAP)A and VAPB through the two phenylalanines in an acidic tract (FFAT)-like motif in the C-terminal region of CDIP1, mutations of which resulted in reduction of CDIP1-induced cell death. Therefore, our findings suggest that different expression levels of ALG-2, ESCRT-I subunits, VAPA and VAPB may have an impact on sensitivity of anticancer drugs associated with CDIP1 expression.

scholarly journals TaMCA4, a Novel Wheat Metacaspase Gene Functions in Programmed Cell Death Induced by the Fungal Pathogen Puccinia striiformis f. sp. tritici

2012 ◽  
Vol 25 (6) ◽  
pp. 755-764 ◽  
Author(s):  
Xiaodong Wang ◽  
Xiaojie Wang ◽  
Hao Feng ◽  
Chunlei Tang ◽  
Pengfei Bai ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Fungal Pathogen ◽  
Puccinia Striiformis ◽  
Transcript Level ◽  
Structural Features ◽  
Virus Induced Gene Silencing ◽  
Wheat Leaves ◽  
Multicellular Organisms ◽  
Bax Gene

Programmed cell death (PCD) is a physiological process to remove redundant or harmful cells, for the development of multicellular organisms, or for restricting the spread of pathogens (hypersensitive response). Metacaspases are cysteine-dependent proteases which play an essential role in PCD. Triticum aestivum metacaspase 4 (TaMCA4) is a type II metacaspase gene cloned from ‘Suwon11’ wheat, with typical structural features such as peptidase C14 caspase domain and a long linker sequence between the two subunits. Transient expression of TaMCA4 in tobacco leaves failed to induce PCD directly but enhanced cell death triggered by a mouse Bax gene or a candidate effector gene from Puccinia striiformis f. sp. tritici. Enhancement of PCD was also observed in wheat leaves co-bombarded with TaMCA4. When challenged with the avirulent race of P. striiformis f. sp. tritici, the expression level of TaMCA4 in wheat leaves was sharply upregulated, whereas the transcript level was not significantly induced by the virulent race. Moreover, knocking down TaMCA4 expression by virus-induced gene silencing enhanced the susceptibility of Suwon11 to the avirulent race of P. striiformis f. sp. tritici and reduced the necrotic area at infection sites.

scholarly journals Secretome Analysis and In Planta Expression of Salivary Proteins Identify Candidate Effectors from the Brown Planthopper Nilaparvata lugens

2019 ◽  
Vol 32 (2) ◽  
pp. 227-239 ◽  
Author(s):  
Weiwei Rao ◽  
Xiaohong Zheng ◽  
Bingfang Liu ◽  
Qin Guo ◽  
Jianping Guo ◽  
...  
Keyword(s):  
Cell Death ◽  
Expression Analysis ◽  
Plant Pathogens ◽  
Critical Role ◽  
Brown Planthopper ◽  
Ectopic Expression ◽  
Nilaparvata Lugens ◽  
Effector Proteins ◽  
Salivary Proteins ◽  
Secretome Analysis

The brown planthopper (BPH), Nilaparvata lugens (Stål), is a phloem sap-feeding insect. During feeding on rice plants, BPH secretes salivary proteins with potential effector functions, which may play a critical role in the plant–insect interactions. However, a limited number of BPH effector proteins have been identified to date. Here, we sequenced the salivary gland transcriptomes of five BPH populations and subsequently established a N. lugens secretome consisting of 1,140 protein-encoding genes. Secretome analysis revealed the presence of both conserved and rapidly evolving salivary proteins. A screen for potential effectors that elicit responses in the plant was performed via the transient expression analysis of 64 BPH salivary proteins in Nicotiana benthamiana leaves and rice protoplasts. The salivary proteins Nl12, Nl16, Nl28, and Nl43 induced cell death, whereas Nl40 induced chlorosis and Nl32 induced a dwarf phenotype in N. benthamiana, indicating effector properties of these proteins. Ectopic expression of the six salivary proteins in N. benthamiana upregulated expression of defense-related genes and callose deposition. Tissue expression analysis showed a higher expression level of the six candidate effectors in salivary glands than in other tissues. Subcellular localization and analysis of the domain required for cell death showed a diverse structure of the six effectors. Nl28, Nl40, and Nl43 are N. lugens specific; in contrast, Nl12, Nl16, and Nl32 are conserved among insects. The Nl40 family has numerous isoforms produced by alternative splicing, exemplifying rapid evolution and expansion of effector proteins in the BPH. Our results suggest a potential large effector repertoire in BPH and a higher level of effector conservation exist in BPH compared with that in plant pathogens.

scholarly journals Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer

2020 ◽  
pp. jmedgenet-2019-106739 ◽  
Author(s):  
Honglin Song ◽  
Ed M Dicks ◽  
Jonathan Tyrer ◽  
Maria Intermaggio ◽  
Georgia Chenevix-Trench ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Candidate Genes ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
European Ancestry ◽  
Ovarian Cancer Risk ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Deleterious Mutations ◽  
Increased Risk

PurposeThe known epithelial ovarian cancer (EOC) susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting that other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes.MethodsWe sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases versus controls were further examined in an independent set of 14 135 EOC cases and 28 655 controls from the Ovarian Cancer Association Consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics.ResultsThe ORs associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 to 5.68; p=0.00068), 1.99 for POLK (95% CI 1.15 to 3.43; p=0.014) and 4.07 for SLX4 (95% CI 1.34 to 12.4; p=0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 to 1.00, p=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive.ConclusionsWe have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.

scholarly journals Tobacco, Genetic Susceptibility and Lung cancer

2010 ◽  
Vol 3 ◽  
pp. TUI.S2819
Author(s):  
Ravindran Ankathil
Keyword(s):  
Risk Factors ◽  
Lung Cancer ◽  
Genetic Susceptibility ◽  
Candidate Genes ◽  
Genetic Polymorphisms ◽  
High Frequency ◽  
Association Studies ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Genome Wide Association Studies

Exposure to tobacco smoke is an established risk factor for lung cancer, although a possible role for genetic susceptibility in the development of lung cancer has been inferred from familial clustering of the disease and segregation analysis. Findings of familial aggregation and statistical evidence for a major susceptibility gene have led to the search for high penetrant, rare, single genes and low penetrant, high frequency susceptibility genes for lung cancer. The relatively small number of linkage studies conducted to date, have identified potential lung cancer susceptibility loci on chromosomes 6q, 12p, and 19q. A variety of studies have examined single nucleotide polymorphisms of several low penetrant, high frequency genes encoding for enzymes involved in the metabolism of carcinogens and DNA damage repair, as likely candidate susceptibility genes. These studies have produced somewhat conflicting findings and, when significant, only modest associations have been reported. Relatively few studies have looked for potential gene-environment interactions, explored associations between two or more genetic polymorphisms or evaluated interactions between genetic polymorphisms and endogenous risk factors. Few large scale genome wide association studies conducted recently have provided evidence that common variation on chromosome 15q25.1, 5p15.33 and 6p21.33 influences lung cancer risk and cancer types with strong environmental risk factors. It is hoped that newer research strategies, selecting candidate genes within pathways and genotype at multiple markers within a gene, employing new technologies, may allow complete coverage of the variation within candidate genes in multiple pathways and to unravel the genetic susceptibility to lung cancer. This knowledge could, in turn, be used to identify persons at risk, to individualize treatments such as chemoprevention, to personalize harms of smoking and to motivate cessation.

scholarly journals WtsE, an AvrE-Family Effector Protein from Pantoea stewartii subsp. stewartii, Causes Disease-Associated Cell Death in Corn and Requires a Chaperone Protein for Stability

2006 ◽  
Vol 19 (10) ◽  
pp. 1092-1102 ◽  
Author(s):  
Jong Hyun Ham ◽  
Doris R. Majerczak ◽  
Angel S. Arroyo-Rodriguez ◽  
David M. Mackey ◽  
David L. Coplin
Keyword(s):  
Cell Death ◽  
Sweet Corn ◽  
Coli Strain ◽  
Effector Proteins ◽  
Erwinia Chrysanthemi ◽  
Endoplasmic Reticulum Membrane ◽  
E Coli ◽  
Pantoea Stewartii ◽  
C Terminus ◽  
Efficient Delivery

The pathogenicity of Pantoea stewartii subsp. stewartii to sweet corn and maize requires a Hrp type III secretion system. In this study, we genetically and functionally characterized a disease-specific (Dsp) effector locus, composed of wtsE and wtsF, that is adjacent to the hrp gene cluster. WtsE, a member of the AvrE family of effector proteins, was essential for pathogenesis on corn and was complemented by DspA/E from Erwinia amylovora. An intact C-terminus of WtsE, which contained a putative endoplasmic reticulum membrane retention signal, was important for function of WtsE. Delivery of WtsE into sweet corn leaves by an Escherichia coli strain carrying the hrp cluster of Erwinia chrysanthemi caused water-soaking and necrosis. WtsE-induced cell death was not inhibited by cycloheximide treatment, unlike the hypersensitive response caused by a known Avr protein, AvrRxo1. WtsF, the putative chaperone of WtsE, was not required for secretion of WtsE from P. stewartii, and the virulence of wtsF mutants was reduced only at low inoculum concentrations. However, WtsF was required for full accumulation of WtsE within the bacteria at low temperatures. In contrast, WtsF was needed for efficient delivery of WtsE from E. coli via the Erwinia chrysanthemi Hrp system.

Management of germline findings revealed throughout the course of tumor-normal whole genome sequencing in oncology.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13113-e13113
Author(s):  
Howard John Lim ◽  
Kasmintan A Schrader ◽  
Sean Young ◽  
Jessica Nelson ◽  
Alexandra Fok ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Susceptibility ◽  
Susceptibility Gene ◽  
Susceptibility Genes ◽  
Genomic Research ◽  
Whole Genome ◽  
Pathogenic Variants ◽  
Cancer Susceptibility Genes

e13113 Background: The Personalized OncoGenomics (POG) project at the BC Cancer Agency utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide personalized treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign or of unknown significance (VUS). We have developed a process for evaluating and returning presumed pathogenic variants in known cancer susceptibility genes to patients, for counseling and validation in a clinical-accredited laboratory. Methods: Patients receive germline cancer related information as part of the consent process for participation in the POG program. A sub-committee comprised of medical geneticists, bioinformaticians, pathologists, oncologists and an ethicist review the germline results. Any variants suspicious of being an artifact undergo a technical validation step. Presumed pathogenic findings of known cancer susceptibility genes are returned to the patient by their treating oncologist and patients are referred to the Hereditary Cancer Program (HCP), for genetic counseling and clinical confirmation. Results: From June 2012 - January 2017 – 466 patients have consented to the project. To date, 39 cases (8.4%) had at least one variant that was deemed pathogenic, 86 cases had at least one VUS in a known cancer susceptibility gene. 11 out of 23 cases (47.8%) with high penetrance mutations were already known to HCP. All VUS were reviewed by the sub-committee taking in to consideration the VUS and clinical context. 8 of the subjects with pathogenic results and 3 with VUS were known to HCP before POG data was generated. A VUS in 7 cases (1.5%) was returned after review. Conclusions: The number of pathogenic variants in known cancer susceptibility genes is consistent with published oncology results. We created a process to manage clinically relevant germline findings discovered during the course of genomic research to ensure appropriate care for patients. Genetic counseling within HCP and validation of variants in the clinically accredited Cancer Genetics Laboratory enables seamless return of research generated clinically relevant germline results to affected subjects. Clinical trial information: NCT02155621.

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