Global functional analyses of cellular responses to pore-forming toxins.
Here we present the first global functional analysis of cellular responses to pore-forming toxins (PFTs). PFTs are uniquely important bacterial virulence factors, comprising the single largest class of bacterial protein toxins and being important for the pathogenesis in humans of many Gram positive...
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2011
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oai:doaj.org-article:33afd7ffdcaa4c2b8670aa81a8cc9d3c2021-11-18T06:03:32ZGlobal functional analyses of cellular responses to pore-forming toxins.1553-73661553-737410.1371/journal.ppat.1001314https://doaj.org/article/33afd7ffdcaa4c2b8670aa81a8cc9d3c2011-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21408619/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Here we present the first global functional analysis of cellular responses to pore-forming toxins (PFTs). PFTs are uniquely important bacterial virulence factors, comprising the single largest class of bacterial protein toxins and being important for the pathogenesis in humans of many Gram positive and Gram negative bacteria. Their mode of action is deceptively simple, poking holes in the plasma membrane of cells. The scattered studies to date of PFT-host cell interactions indicate a handful of genes are involved in cellular defenses to PFTs. How many genes are involved in cellular defenses against PFTs and how cellular defenses are coordinated are unknown. To address these questions, we performed the first genome-wide RNA interference (RNAi) screen for genes that, when knocked down, result in hypersensitivity to a PFT. This screen identifies 106 genes (∼0.5% of genome) in seven functional groups that protect Caenorhabditis elegans from PFT attack. Interactome analyses of these 106 genes suggest that two previously identified mitogen-activated protein kinase (MAPK) pathways, one (p38) studied in detail and the other (JNK) not, form a core PFT defense network. Additional microarray, real-time PCR, and functional studies reveal that the JNK MAPK pathway, but not the p38 MAPK pathway, is a key central regulator of PFT-induced transcriptional and functional responses. We find C. elegans activator protein 1 (AP-1; c-jun, c-fos) is a downstream target of the JNK-mediated PFT protection pathway, protects C. elegans against both small-pore and large-pore PFTs and protects human cells against a large-pore PFT. This in vivo RNAi genomic study of PFT responses proves that cellular commitment to PFT defenses is enormous, demonstrates the JNK MAPK pathway as a key regulator of transcriptionally-induced PFT defenses, and identifies AP-1 as the first cellular component broadly important for defense against large- and small-pore PFTs.Cheng-Yuan KaoFerdinand C O LosDanielle L HuffmanShinichiro WachiNicole KloftMatthias HusmannValbona KarabrahimiJean-Louis SchwartzAudrey BellierChristine HaYoun SagongHui FanPartho GhoshMindy HsiehChih-Shen HsuLi ChenRaffi V AroianPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 3, p e1001314 (2011) |
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| collection |
DOAJ |
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EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Cheng-Yuan Kao Ferdinand C O Los Danielle L Huffman Shinichiro Wachi Nicole Kloft Matthias Husmann Valbona Karabrahimi Jean-Louis Schwartz Audrey Bellier Christine Ha Youn Sagong Hui Fan Partho Ghosh Mindy Hsieh Chih-Shen Hsu Li Chen Raffi V Aroian Global functional analyses of cellular responses to pore-forming toxins. |
| description |
Here we present the first global functional analysis of cellular responses to pore-forming toxins (PFTs). PFTs are uniquely important bacterial virulence factors, comprising the single largest class of bacterial protein toxins and being important for the pathogenesis in humans of many Gram positive and Gram negative bacteria. Their mode of action is deceptively simple, poking holes in the plasma membrane of cells. The scattered studies to date of PFT-host cell interactions indicate a handful of genes are involved in cellular defenses to PFTs. How many genes are involved in cellular defenses against PFTs and how cellular defenses are coordinated are unknown. To address these questions, we performed the first genome-wide RNA interference (RNAi) screen for genes that, when knocked down, result in hypersensitivity to a PFT. This screen identifies 106 genes (∼0.5% of genome) in seven functional groups that protect Caenorhabditis elegans from PFT attack. Interactome analyses of these 106 genes suggest that two previously identified mitogen-activated protein kinase (MAPK) pathways, one (p38) studied in detail and the other (JNK) not, form a core PFT defense network. Additional microarray, real-time PCR, and functional studies reveal that the JNK MAPK pathway, but not the p38 MAPK pathway, is a key central regulator of PFT-induced transcriptional and functional responses. We find C. elegans activator protein 1 (AP-1; c-jun, c-fos) is a downstream target of the JNK-mediated PFT protection pathway, protects C. elegans against both small-pore and large-pore PFTs and protects human cells against a large-pore PFT. This in vivo RNAi genomic study of PFT responses proves that cellular commitment to PFT defenses is enormous, demonstrates the JNK MAPK pathway as a key regulator of transcriptionally-induced PFT defenses, and identifies AP-1 as the first cellular component broadly important for defense against large- and small-pore PFTs. |
| format |
article |
| author |
Cheng-Yuan Kao Ferdinand C O Los Danielle L Huffman Shinichiro Wachi Nicole Kloft Matthias Husmann Valbona Karabrahimi Jean-Louis Schwartz Audrey Bellier Christine Ha Youn Sagong Hui Fan Partho Ghosh Mindy Hsieh Chih-Shen Hsu Li Chen Raffi V Aroian |
| author_facet |
Cheng-Yuan Kao Ferdinand C O Los Danielle L Huffman Shinichiro Wachi Nicole Kloft Matthias Husmann Valbona Karabrahimi Jean-Louis Schwartz Audrey Bellier Christine Ha Youn Sagong Hui Fan Partho Ghosh Mindy Hsieh Chih-Shen Hsu Li Chen Raffi V Aroian |
| author_sort |
Cheng-Yuan Kao |
| title |
Global functional analyses of cellular responses to pore-forming toxins. |
| title_short |
Global functional analyses of cellular responses to pore-forming toxins. |
| title_full |
Global functional analyses of cellular responses to pore-forming toxins. |
| title_fullStr |
Global functional analyses of cellular responses to pore-forming toxins. |
| title_full_unstemmed |
Global functional analyses of cellular responses to pore-forming toxins. |
| title_sort |
global functional analyses of cellular responses to pore-forming toxins. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/33afd7ffdcaa4c2b8670aa81a8cc9d3c |
| work_keys_str_mv |
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