Anthrax lethal factor cleaves regulatory subunits of phosphoinositide-3 kinase to contribute to toxin lethality

Anthrax lethal toxin (LT), produced by Bacillus anthracis , comprises a receptor-binding moiety, protective antigen and the lethal factor (LF) protease 1 , 2 . Although LF is known to cleave mitogen-activated protein kinase kinases (MEKs/MKKs) and some variants of the NLRP1 inflammasome sensor, targ...

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Published inNature microbiology Vol. 5; no. 12; pp. 1464 - 1471
Main Authors Mendenhall, Megan A., Liu, Shihui, Portley, Makayla K., O’Mard, Danielle, Fattah, Rasem, Szabo, Roman, Bugge, Thomas H., Khillan, Jaspal S., Leppla, Stephen H., Moayeri, Mahtab
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Published London Nature Publishing Group UK 01.12.2020
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Abstract Anthrax lethal toxin (LT), produced by Bacillus anthracis , comprises a receptor-binding moiety, protective antigen and the lethal factor (LF) protease 1 , 2 . Although LF is known to cleave mitogen-activated protein kinase kinases (MEKs/MKKs) and some variants of the NLRP1 inflammasome sensor, targeting of these pathways does not explain the lethality of anthrax toxin 1 , 2 . Here we report that the regulatory subunits of phosphoinositide-3 kinase (PI3K)—p85α (PIK3R1) and p85β (PIK3R2) 3 , 4 —are substrates of LF. Cleavage of these proteins in a proline-rich region between their N-terminal Src homology and Bcr homology domains disrupts homodimer formation and impacts PI3K signalling. Mice carrying a mutated p85α that cannot be cleaved by LF show a greater resistance to anthrax toxin challenge. The LF(W271A) mutant cleaves p85α with lower efficiency and is non-toxic to mice but can regain lethality when combined with PI3K pathway inhibitors. We provide evidence that LF targets two signalling pathways that are essential for growth and metabolism and that the disabling of both pathways is likely necessary for lethal anthrax infection. Cellular targets of anthrax lethal factor are identified to reveal the molecular basis of toxin-induced death.
AbstractList Anthrax lethal toxin (LT), produced by Bacillus anthracis, comprises a receptor-binding moiety, protective antigen and the lethal factor (LF) protease1,2. Although LF is known to cleave mitogen-activated protein kinase kinases (MEKs/MKKs) and some variants of the NLRP1 inflammasome sensor, targeting of these pathways does not explain the lethality of anthrax toxin1,2. Here we report that the regulatory subunits of phosphoinositide-3 kinase (PI3K)-p85α (PIK3R1) and p85β (PIK3R2)3,4-are substrates of LF. Cleavage of these proteins in a proline-rich region between their N-terminal Src homology and Bcr homology domains disrupts homodimer formation and impacts PI3K signalling. Mice carrying a mutated p85α that cannot be cleaved by LF show a greater resistance to anthrax toxin challenge. The LF(W271A) mutant cleaves p85α with lower efficiency and is non-toxic to mice but can regain lethality when combined with PI3K pathway inhibitors. We provide evidence that LF targets two signalling pathways that are essential for growth and metabolism and that the disabling of both pathways is likely necessary for lethal anthrax infection.Anthrax lethal toxin (LT), produced by Bacillus anthracis, comprises a receptor-binding moiety, protective antigen and the lethal factor (LF) protease1,2. Although LF is known to cleave mitogen-activated protein kinase kinases (MEKs/MKKs) and some variants of the NLRP1 inflammasome sensor, targeting of these pathways does not explain the lethality of anthrax toxin1,2. Here we report that the regulatory subunits of phosphoinositide-3 kinase (PI3K)-p85α (PIK3R1) and p85β (PIK3R2)3,4-are substrates of LF. Cleavage of these proteins in a proline-rich region between their N-terminal Src homology and Bcr homology domains disrupts homodimer formation and impacts PI3K signalling. Mice carrying a mutated p85α that cannot be cleaved by LF show a greater resistance to anthrax toxin challenge. The LF(W271A) mutant cleaves p85α with lower efficiency and is non-toxic to mice but can regain lethality when combined with PI3K pathway inhibitors. We provide evidence that LF targets two signalling pathways that are essential for growth and metabolism and that the disabling of both pathways is likely necessary for lethal anthrax infection.
Anthrax lethal toxin (LT), produced by Bacillus anthracis, comprises a receptor-binding moiety, protective antigen and the lethal factor (LF) protease1,2. Although LF is known to cleave mitogen-activated protein kinase kinases (MEKs/MKKs) and some variants of the NLRP1 inflammasome sensor, targeting of these pathways does not explain the lethality of anthrax toxin1,2. Here we report that the regulatory subunits of phosphoinositide-3 kinase (PI3K)—p85α (PIK3R1) and p85β (PIK3R2)3,4—are substrates of LF. Cleavage of these proteins in a proline-rich region between their N-terminal Src homology and Bcr homology domains disrupts homodimer formation and impacts PI3K signalling. Mice carrying a mutated p85α that cannot be cleaved by LF show a greater resistance to anthrax toxin challenge. The LF(W271A) mutant cleaves p85α with lower efficiency and is non-toxic to mice but can regain lethality when combined with PI3K pathway inhibitors. We provide evidence that LF targets two signalling pathways that are essential for growth and metabolism and that the disabling of both pathways is likely necessary for lethal anthrax infection.Cellular targets of anthrax lethal factor are identified to reveal the molecular basis of toxin-induced death.
Anthrax lethal toxin (LT), produced by Bacillus anthracis , comprises a receptor-binding moiety, protective antigen and the lethal factor (LF) protease 1 , 2 . Although LF is known to cleave mitogen-activated protein kinase kinases (MEKs/MKKs) and some variants of the NLRP1 inflammasome sensor, targeting of these pathways does not explain the lethality of anthrax toxin 1 , 2 . Here we report that the regulatory subunits of phosphoinositide-3 kinase (PI3K)—p85α (PIK3R1) and p85β (PIK3R2) 3 , 4 —are substrates of LF. Cleavage of these proteins in a proline-rich region between their N-terminal Src homology and Bcr homology domains disrupts homodimer formation and impacts PI3K signalling. Mice carrying a mutated p85α that cannot be cleaved by LF show a greater resistance to anthrax toxin challenge. The LF(W271A) mutant cleaves p85α with lower efficiency and is non-toxic to mice but can regain lethality when combined with PI3K pathway inhibitors. We provide evidence that LF targets two signalling pathways that are essential for growth and metabolism and that the disabling of both pathways is likely necessary for lethal anthrax infection. Cellular targets of anthrax lethal factor are identified to reveal the molecular basis of toxin-induced death.
Anthrax lethal toxin (LT), produced by Bacillus anthracis , comprises a receptor-binding moiety, protective antigen and the lethal factor (LF) protease 1 , 2 . Although LF is known to cleave mitogen-activated protein kinase kinases (MEKs/MKKs) and some variants of the NLRP1 inflammasome sensor, targeting of these pathways does not explain the lethality of anthrax toxin 1 , 2 . Here we report that the regulatory subunits of phosphoinositide-3 kinase (PI3K)—p85α (PIK3R1) and p85β (PIK3R2) 3 , 4 —are substrates of LF. Cleavage of these proteins in a proline-rich region between their N-terminal Src homology and Bcr homology domains disrupts homodimer formation and impacts PI3K signalling. Mice carrying a mutated p85α that cannot be cleaved by LF show a greater resistance to anthrax toxin challenge. The LF(W271A) mutant cleaves p85α with lower efficiency and is non-toxic to mice but can regain lethality when combined with PI3K pathway inhibitors. We provide evidence that LF targets two signalling pathways that are essential for growth and metabolism and that the disabling of both pathways is likely necessary for lethal anthrax infection.
Anthrax lethal toxin (LT), produced by Bacillus anthracis, comprises a receptor-binding moiety, protective antigen and the lethal factor (LF) protease . Although LF is known to cleave mitogen-activated protein kinase kinases (MEKs/MKKs) and some variants of the NLRP1 inflammasome sensor, targeting of these pathways does not explain the lethality of anthrax toxin . Here we report that the regulatory subunits of phosphoinositide-3 kinase (PI3K)-p85α (PIK3R1) and p85β (PIK3R2) -are substrates of LF. Cleavage of these proteins in a proline-rich region between their N-terminal Src homology and Bcr homology domains disrupts homodimer formation and impacts PI3K signalling. Mice carrying a mutated p85α that cannot be cleaved by LF show a greater resistance to anthrax toxin challenge. The LF(W271A) mutant cleaves p85α with lower efficiency and is non-toxic to mice but can regain lethality when combined with PI3K pathway inhibitors. We provide evidence that LF targets two signalling pathways that are essential for growth and metabolism and that the disabling of both pathways is likely necessary for lethal anthrax infection.
Author Portley, Makayla K.
Szabo, Roman
Fattah, Rasem
Khillan, Jaspal S.
Liu, Shihui
O’Mard, Danielle
Leppla, Stephen H.
Moayeri, Mahtab
Bugge, Thomas H.
Mendenhall, Megan A.
AuthorAffiliation 4 Mouse Genetics and Gene Modification Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
1 Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
2 Department of Medicine, Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, PA, USA
3 Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
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M.M. conceived the project. M.M. and M.A.M. designed and performed experiments and analysed the data. M.K.P. and D.O. performed experiments. S.L. designed experiments, performed preliminary mutant LF studies and analysed the data. S.H.L. designed constructs, contributed reagents and analysed the data. R.F. purified proteins and performed mass spectrometry analyses. R.S., T.H.B. and J.S.K. designed and created the knockin mouse model. M.M., M.A.M. and S.H.L. wrote and edited the manuscript with input from all authors.
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Snippet Anthrax lethal toxin (LT), produced by Bacillus anthracis , comprises a receptor-binding moiety, protective antigen and the lethal factor (LF) protease 1 , 2 ....
Anthrax lethal toxin (LT), produced by Bacillus anthracis, comprises a receptor-binding moiety, protective antigen and the lethal factor (LF) protease ....
Anthrax lethal toxin (LT), produced by Bacillus anthracis, comprises a receptor-binding moiety, protective antigen and the lethal factor (LF) protease1,2....
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StartPage 1464
SubjectTerms 1-Phosphatidylinositol 3-kinase
101/1
13
13/106
42/70
45/41
631/326/421
631/326/88
692/699/1785
692/699/255
82
82/29
82/58
82/80
82/83
96/109
96/34
96/95
Amino Acid Motifs
Animals
Anthrax
Anthrax - enzymology
Anthrax - genetics
Anthrax - microbiology
Anthrax lethal toxin
Antigens, Bacterial - metabolism
Antigens, Bacterial - toxicity
Bacillus anthracis - enzymology
Bacillus anthracis - metabolism
Bacterial Toxins - metabolism
Bacterial Toxins - toxicity
Biomedical and Life Sciences
Class Ia Phosphatidylinositol 3-Kinase - chemistry
Class Ia Phosphatidylinositol 3-Kinase - genetics
Class Ia Phosphatidylinositol 3-Kinase - metabolism
Homology
Humans
Infectious Diseases
Inflammasomes
Kinases
Lethal factor
Lethality
Letter
Life Sciences
Male
MAP kinase
Medical Microbiology
Mice
Mice, Inbred C57BL
Microbiology
MKKS protein
Parasitology
Peptide Hydrolases - genetics
Peptide Hydrolases - metabolism
Phosphatidylinositol 3-Kinases - chemistry
Phosphatidylinositol 3-Kinases - genetics
Phosphatidylinositol 3-Kinases - metabolism
Proline
Protective antigen
Protein kinase
Regulatory subunits
Signal transduction
Virology
Title Anthrax lethal factor cleaves regulatory subunits of phosphoinositide-3 kinase to contribute to toxin lethality
URI https://link.springer.com/article/10.1038/s41564-020-0782-1
https://www.ncbi.nlm.nih.gov/pubmed/32895527
https://www.proquest.com/docview/2475051852
https://www.proquest.com/docview/2440905499
https://pubmed.ncbi.nlm.nih.gov/PMC11540063
Volume 5
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