Mitochondrial Proteins Bnip3 and Bnip3L Are Involved in Anthrax Lethal Toxin-induced Macrophage Cell Death

Anthrax lethal toxin (LeTx) induces rapid cell death of RAW246.7 macrophages. We recently found that a small population of these macrophages is spontaneously and temporally refractory to LeTx-induced cytotoxicity. Analysis of genome-wide transcripts of a resistant clone before and after regaining LeTx sensitivity revealed that a reduction of two closely related mitochondrial proteins, Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (Bnip3) and Bnip3-like (Bnip3L), correlates with LeTx resistance. Down-regulation of Bnip3 and Bnip3L was also found in “toxin-induced resistance” whereby sublethal doses of LeTx induce resistance to subsequent exposure to cytolytic toxin doses. The role of Bnip3 and Bnip3L in LeTx-induced cell death was confirmed by showing that overexpression of either Bnip3 or Bnip3L rendered the resistant cells susceptible to LeTx, whereas down-regulation of Bnip3 and Bnip3L in wild-type macrophages conferred resistance. The down-regulation of Bnip3 and Bnip3L mRNAs by LeTx occurred at both transcriptional and mRNA stability levels. Inhibition of the p38 pathway by lethal factor was responsible for the destabilization of Bnip3/Bnip3L mRNAs as confirmed by showing that p38 inhibitors stabilized Bnip3 and Bnip3L mRNAs and conferred resistance to LeTx cytotoxicity. Therefore, Bnip3/Bnip3L play a crucial role in LeTx-induced cytotoxicity, and down-regulation of Bnip3/Bnip3L is a mechanism of spontaneous or toxin-induced resistance of macrophages. Anthrax lethal toxin (LeTx) induces rapid cell death of RAW246.7 macrophages. We recently found that a small population of these macrophages is spontaneously and temporally refractory to LeTx-induced cytotoxicity. Analysis of genome-wide transcripts of a resistant clone before and after regaining LeTx sensitivity revealed that a reduction of two closely related mitochondrial proteins, Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (Bnip3) and Bnip3-like (Bnip3L), correlates with LeTx resistance. Down-regulation of Bnip3 and Bnip3L was also found in “toxin-induced resistance” whereby sublethal doses of LeTx induce resistance to subsequent exposure to cytolytic toxin doses. The role of Bnip3 and Bnip3L in LeTx-induced cell death was confirmed by showing that overexpression of either Bnip3 or Bnip3L rendered the resistant cells susceptible to LeTx, whereas down-regulation of Bnip3 and Bnip3L in wild-type macrophages conferred resistance. The down-regulation of Bnip3 and Bnip3L mRNAs by LeTx occurred at both transcriptional and mRNA stability levels. Inhibition of the p38 pathway by lethal factor was responsible for the destabilization of Bnip3/Bnip3L mRNAs as confirmed by showing that p38 inhibitors stabilized Bnip3 and Bnip3L mRNAs and conferred resistance to LeTx cytotoxicity. Therefore, Bnip3/Bnip3L play a crucial role in LeTx-induced cytotoxicity, and down-regulation of Bnip3/Bnip3L is a mechanism of spontaneous or toxin-induced resistance of macrophages. Anthrax is often a fatal bacterial infection that occurs after inhalation of endospores of Bacillus anthracis, a Gram-positive soil bacterium (1Dixon T.C. Meselson M. Guillemin J. Hanna P.C. N. Engl. J. Med. 1999; 341: 815-826Crossref PubMed Scopus (895) Google Scholar). Endospores germinate within phagocytes becoming metabolically active vegetative bacteria (2Guidi-Rontani C. Weber-Levy M. Labruyere E. Mock M. Mol. Microbiol. 1999; 31: 9-17Crossref PubMed Scopus (277) Google Scholar, 3Dixon T.C. Fadl A.A. Koehler T.M. Swanson J.A. Hanna P.C. Cell. Microbiol. 2000; 2: 453-463Crossref PubMed Scopus (194) Google Scholar) that are released from the cells, multiply in the lymphatic system, and enter the bloodstream, causing severe septicemia and toxemia (1Dixon T.C. Meselson M. Guillemin J. Hanna P.C. N. Engl. J. Med. 1999; 341: 815-826Crossref PubMed Scopus (895) Google Scholar, 4Albrink W.S. Goodlow R.J. Am. J. Pathol. 1959; 35: 1055-1065PubMed Google Scholar). Several virulence factors are encoded in B. anthracis plasmids including the anthrax lethal toxin (LeTx) 4The abbreviations used are: LeTxanthrax lethal toxinPAprotective antigenLFlethal factorTIRtoxin-induced resistanceBnip3Bcl-2/adenovirus E1B 19-kDa interacting protein 3Bnip3LBnip3-likeJnkc-Jun N-terminal kinaseErkextracellular signal-regulated kinaseMekmitogen-activated protein kinase/extracellular signal-regulated kinase kinaseMAPKmitogen-activated protein kinaseMTT3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromideMOPS4-morpholinepropanesulfonic acidsiRNAsmall interfering RNAGFPgreen fluorescent proteinSBSB202190BH3Bcl-2 homology 3AREAU-rich element. and edema toxin, which contribute to the survival of vegetative bacteria and toxemia (5Baldari C.T. Tonello F. Paccani S.R. Montecucco C. Trends Immunol. 2006; 27: 434-440Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 6Tournier J.N. Quesnel-Hellmann A. Cleret A. Vidal D.R. Cell. Microbiol. 2007; 9: 555-565Crossref PubMed Scopus (64) Google Scholar, 7Pezard C. Berche P. Mock M. Infect. Immun. 1991; 59: 3472-3477Crossref PubMed Google Scholar). LeTx and edema toxin are binary A-B toxins comprising protective antigen (PA) and lethal factor (LF) or edema factor, respectively. PA is a molecular transporter allowing receptor-mediated entry and release of LF or edema factor into the cytosol. Edema factor has adenylate cyclase activity (8Leppla S.H. Proc. Natl. Acad. Sci. U. S. A. 1982; 79: 3162-3166Crossref PubMed Scopus (766) Google Scholar), whereas LF is a zinc metalloprotease that cleaves the N-terminal end of Mek1 to -7, except Mek5, resulting in the inactivation of these kinases. LF also rapidly induces the release of interleukin-1β and interleukin-18 likely through activation of caspase-1 (9Cordoba-Rodriguez R. Fang H. Lankford C.S. Frucht D.M. J. Biol. Chem. 2004; 279: 20563-20566Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). LeTx and edema toxin by themselves are toxic to animals, but both together further enhance toxin lethality (6Tournier J.N. Quesnel-Hellmann A. Cleret A. Vidal D.R. Cell. Microbiol. 2007; 9: 555-565Crossref PubMed Scopus (64) Google Scholar, 7Pezard C. Berche P. Mock M. Infect. Immun. 1991; 59: 3472-3477Crossref PubMed Google Scholar, 10Firoved A.M. Miller G.F. Moayeri M. Kakkar R. Shen Y. Wiggins J.F. McNally E.M. Tang W.J. Leppla S.H. Am. J. Pathol. 2005; 167: 1309-1320Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). anthrax lethal toxin protective antigen lethal factor toxin-induced resistance Bcl-2/adenovirus E1B 19-kDa interacting protein 3 Bnip3-like c-Jun N-terminal kinase extracellular signal-regulated kinase mitogen-activated protein kinase/extracellular signal-regulated kinase kinase mitogen-activated protein kinase 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 4-morpholinepropanesulfonic acid small interfering RNA green fluorescent protein SB202190 Bcl-2 homology 3 AU-rich element. Macrophages are the first immune cells encountering the spores (11Moayeri M. Leppla S.H. Curr. Opin. Microbiol. 2004; 7: 19-24Crossref PubMed Scopus (221) Google Scholar) and key innate immune cells defending against the infection (12Cote C.K. Rea K.M. Norris S.L. van Rooijen N. Welkos S.L. Microb. Pathog. 2004; 37: 169-175Crossref PubMed Scopus (70) Google Scholar, 13Cote C.K. Van Rooijen N. 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Commun. 2002; 293: 349-355Crossref PubMed Scopus (117) Google Scholar) cell death of macrophages, which can contribute to the survival of the vegetative bacteria (3Dixon T.C. Fadl A.A. Koehler T.M. Swanson J.A. Hanna P.C. Cell. Microbiol. 2000; 2: 453-463Crossref PubMed Scopus (194) Google Scholar, 20Dai Z. Sirard J.C. Mock M. Koehler T.M. Mol. Microbiol. 1995; 16: 1171-1181Crossref PubMed Scopus (133) Google Scholar, 21Brittingham K.C. Ruthel G. Panchal R.G. Fuller C.L. Ribot W.J. Hoover T.A. Young H.A. Anderson A.O. Bavari S. J. Immunol. 2005; 174: 5545-5552Crossref PubMed Scopus (112) Google Scholar, 22Guidi-Rontani C. Levy M. Ohayon H. Mock M. Mol. Microbiol. 2001; 42: 931-938Crossref PubMed Scopus (145) Google Scholar). LeTx also mediates animal death after bacterial clearance by antibiotics in experimental infections with spores or live bacteria (23Smith H. Keppie J. Nature. 1954; 173: 869-870Crossref PubMed Scopus (129) Google Scholar). Although the cytotoxic effects of LeTx on macrophages are the for the LeTx toxemia M. D. Young H.A. Leppla S.H. J. 2003; PubMed Scopus Google Scholar, M. Wiggins J. Young H.A. Leppla S.H. Infect. Immun. 2004; PubMed Scopus Google Scholar), of macrophages to LeTx to the sensitivity to LeTx in J. D. Infect. 2004; PubMed Scopus Google Scholar, P.C. D. R.J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) and in Y. M. Anderson C. Am. J. Pathol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). Macrophages from of in the and cell death LeTx rapid necrotic in macrophages from and whereas cell death is found in macrophages from and S.O. Jing Q. Hoebe K. Beutler B. Duesbery N.S. Han J. J. Biol. Chem. 2003; 278: 7413-7421Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, S.L. Infect. Immun. PubMed Google Scholar, G. J. 2007; PubMed Scopus Google Scholar). The mechanism of rapid in susceptible macrophages has by LeTx is in LeTx macrophages and cell cell death S.O. Jing Q. Hoebe K. Beutler B. Duesbery N.S. Han J. J. Biol. Chem. 2003; 278: 7413-7421Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, R. C. G. Mock M. Montecucco C. 1999; PubMed Scopus Google Scholar, K. J. Curr. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), the of the to cell death by LeTx LeTx sensitivity in of as a factor that rapid LeTx 2006; PubMed Scopus Google Scholar). The a and protein is a of the in innate and Immunol. 2006; 7: PubMed Scopus Google Scholar). induces caspase-1 activation by the that of the protein protein a and was that activation by LF induces caspase-1 and rapid cell death (9Cordoba-Rodriguez R. Fang H. Lankford C.S. Frucht D.M. J. Biol. Chem. 2004; 279: 20563-20566Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 2006; PubMed Scopus Google Scholar). However, the mechanism by which caspase-1 induces rapid cell death to Several in LeTx cytotoxic cells mitochondrial A. J. 2006; PubMed Scopus Google Scholar), and of S. W.S. Biol. Toxicol. 2000; 16: PubMed Scopus Google Scholar, R. Y. Leppla S.H. A.M. Infect. Immun. PubMed Google Scholar, P.C. R.J. Mol. Med. PubMed Google Scholar, P.C. S. R.J. Mol. Biol. Cell. PubMed Scopus Google Scholar). on including the G. Leppla S.H. Infect. Immun. 1999; PubMed Google Scholar) are in LeTx cytotoxicity, but molecular and of LeTx are Macrophages can to LeTx cytotoxicity, a toxin-induced resistance of macrophages with doses of LeTx induces a in which macrophages refractory to with cytolytic doses of LeTx Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). has that the mechanism for either activation in the of LeTx or activity in cells Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). Although the of cells are from LeTx for that a small of RAW246.7 cells resistant to LeTx cytotoxicity, and of the cells resistance for of to The LeTx resistance of the to cells from a resistant clone for Analysis of transcripts from clone and after LeTx resistance revealed that to a reduction in levels. these found two closely related mitochondrial Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (Bnip3) and Bnip3-like also as protein that Bnip3 and Bnip3L play a key role in LeTx-induced in macrophages and that down-regulation of these is a mechanism for which at in is also through of the p38 mitogen-activated protein kinase pathway by LF the first of and LeTx cytotoxicity. and PA in the as P.C. S. R.J. Mol. Biol. Cell. PubMed Scopus Google Scholar). and from and from against the of Mek1 and Bnip3L from and respectively. and of macrophages and macrophages from a from B. in or and at in a of macrophages from as S.O. Jing Q. Hoebe K. Beutler B. Duesbery N.S. Han J. J. Biol. Chem. 2003; 278: 7413-7421Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). cells by macrophages with LeTx LF and for and cells in a and spontaneous LeTx resistance RAW246.7 cells on a and to a cytolytic of LeTx LF and for and on a clone was and of was for LeTx with and LeTx was at macrophages with or LeTx in for and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was at a of at for was and of was to of the at The of cell survival was on the of by with cells as and in and and on for and at for at in by The at for with and at with The and or lethal macrophages with of Bnip3L plasmids A.S. Y. K.M. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar) and of plasmids the cells and with and in cell by on for at for The was into two was for activity in a a The was used for a The activity was on the of and or cells in for The cells for with The cells and on and by of for or was as of Bnip3 and Bnip3L in macrophages was on a RNA was to the of RNA was by and the to the the for and for and for and interfering RNA against Bnip3 and Bnip3L from of cell with was with the to the before at in to a of and with of The used for in the the wild-type p38 and the and as S.O. A. G. Cell. Microbiol. 2006; 8: PubMed Scopus Google Scholar). cells with at of for in and in for Bnip3L from of macrophages. The and the for Bnip3L was by The was with and and into of plasmids was the as for Bnip3 and Bnip3L in LeTx-induced of small population of macrophages is resistant to cytolytic doses of LeTx, but and for LeTx of the resistant cells to LeTx in Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). However, of these cells LeTx resistant for to that from clone before and after regaining LeTx sensitivity in Mek1 and by LeTx Therefore, the resistance was to in toxin and release into of resistant in the resistance a genome-wide the was transcripts from cells before and after regaining LeTx cells from the clone to of the transcripts transcripts with a in of of encoded closely related mitochondrial Bnip3 and Bnip3L protein The reduction of Bnip3 and Bnip3L in the resistant cells was further by The of cell in the resistant cells including and or as and by to wild-type cells the down-regulation of Bnip3 and/or Bnip3L is to the resistance N-terminal Bnip3 and/or Bnip3L in the resistant cells, and these cells also to a cytotoxic of LeTx LF and N-terminal Bnip3 the as wild-type Bnip3 R. Y. Leppla S.H. A.M. Infect. Immun. PubMed Google Scholar), and cells a to these overexpression of Bnip3L cell death in resistant macrophages However, Bnip3L overexpression in with a cytolytic LeTx of cell death in the resistant cells Bnip3 and Bnip3L are for LeTx cytotoxicity, the of Bnip3 and/or Bnip3L in cells Bnip3 and Bnip3L mRNA at in the cells against Bnip3L further that Bnip3L protein in Bnip3L or Bnip3 Bnip3L cells also Down-regulation of the Bnip3L LeTx in of the cells, whereas down-regulation of Bnip3 a was both these the that both Bnip3 and Bnip3L are for LeTx of macrophages. by Down-regulation of Bnip3 and is by which macrophages to sublethal doses of LeTx refractory to subsequent with cytolytic doses of LeTx Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). Bnip3 or Bnip3L is also in macrophages with a sublethal of LeTx LF and that cell with a Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar), for to was whereas by cells as to doses of LeTx as the of Bnip3 and Bnip3L after of LeTx and for at Bnip3L protein also in with mRNA and protein and at to found in The in Bnip3L and protein with the of the and the down-regulation of Bnip3 or Bnip3L is responsible for N-terminal Bnip3 or Bnip3L in cells and with a cytolytic of LeTx LF and that overexpression of either Bnip3 or Bnip3L cells to LeTx, that down-regulation of Bnip3 and Bnip3L is for We further the down-regulation of Bnip3L in cells was to a or mRNA We used a Bnip3L of of to the activity of Bnip3L in wild-type and at activity in cells to wild-type the stability of Bnip3L wild-type or cells with a for and mRNA of Bnip3L by for Bnip3L mRNA in for the Bnip3 mRNA these that Bnip3 and Bnip3L are in and down-regulation of Bnip3L in cells is to activity and mRNA with LeTx in N.S. Leppla S.H. K. G.F. 1998; PubMed Scopus (895) Google Scholar, G. Bernardi L. G. Mock M. Montecucco C. Biochem. J. 2000; PubMed Scopus Google Scholar). is with of cells to a sublethal of LeTx LF and for and of Mek1 and of and p38 for The that in the after LeTx Mek1 at the for to and of and was the for Mek1 to in cells, further LeTx also induces Mek1 down-regulation by interfering with Mek1 We found in Mek1 mRNA wild-type and cells and reduction in Mek1 protein by cells as by of Mek1 of Mek1 protein was by the Mek1 in cells also of Mek1 in the of the Mek1 was to LF cells with the LF at and Mek1 and to LeTx Mek1 was at after cells with LF for susceptible to LeTx that Mek1 N-terminal on LeTx and is for p38 Inhibition to LeTx in of the was in cells of by LeTx is responsible for inhibitors of to the effects in macrophages. cells with of SB202190 p38 or for and to a cytolytic of LeTx LF and was in with a of macrophages from LeTx cytotoxicity. We also these with p38 in the of the resulting from LeTx cells to with the p38 for at before macrophages resistant to LeTx LeTx-induced Inhibition of p38 for the Down-regulation of Bnip3 and p38 LeTx resistance is also through down-regulation of Bnip3 and/or Bnip3L macrophages with or inhibitors or for and mRNA of Bnip3 and Bnip3L in both Bnip3 and Bnip3L mRNAs in but in or macrophages. Bnip3 and Bnip3L mRNAs in a in macrophages in cells whereas the activity of Bnip3L in cells at the as that of wild-type cells in cells and the spontaneous LeTx resistance clone that of that reduction of Bnip3 and Bnip3L by was to of Bnip3 and Bnip3L mRNA is that resistance to LeTx in cells was at in through of Therefore, overexpression of p38 in cells induces of Bnip3 and Bnip3L and to in overexpression of p38 in cells, Bnip3 and Bnip3L mRNA and rendered cells susceptible to LeTx The on LeTx sensitivity in and of Bnip3/Bnip3L in the effects of and the role of Bnip3 and Bnip3L in LeTx-induced in macrophages, macrophages from with a cytolytic of LeTx LF and with or with a sublethal of LeTx LF and doses of p38 or in macrophages, a sublethal of LeTx or the p38 conferred LeTx resistance in the cells and with against Bnip3 and Bnip3L in mRNA and the cells from LeTx-induced that and of Bnip3 and Bnip3L in the are to RAW246.7 macrophages. LeTx-induced Macrophages of Bnip3 and Bnip3L of by LeTx is The cell was from cells of a macrophages. the of Bnip3 and Bnip3L in macrophages, cell that from cells of a macrophages macrophages as as macrophages in LeTx and Mek1 but resistant to LeTx-induced the of Bnip3 and Bnip3L and both Bnip3 and Bnip3L mRNA in cells and Bnip3L protein was in macrophages LeTx a further in Bnip3 and Bnip3L mRNA The mechanism of by LeTx is that mitochondrial Bnip3 and Bnip3L are for the rapid cell death is of macrophages to resistance to cytolytic doses of LeTx by a sublethal of the toxin Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). We also that a sublethal of LeTx Bnip3 and Bnip3L in through a p38 pathway and resistance to LeTx-induced Bnip3 and Bnip3L are mitochondrial that Bcl-2 homology 3 and acid G. J. C. G. J. L. D. A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). proteins, Bnip3 a of mitochondrial that induces a of cell death to mitochondrial of and of C. J. D. J. S. R. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar, R. G. C. J. J.C. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Bnip3L is but can also induce mitochondrial S. S. M. Y. A. Y. 1999; PubMed Scopus Google Scholar) and is in P. S.H. S. M. W.S. Cell. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). We that of Bnip3L and Bnip3 was to LeTx resistance in a small population of macrophages and in toxin-induced resistance cells However, the mechanism of Bnip3 and Bnip3L down-regulation to Although of macrophages with a sublethal of LeTx cell death of Mek1 was in cells that is the of cell which is with S.O. Jing Q. Hoebe K. Beutler B. Duesbery N.S. Han J. J. Biol. Chem. 2003; 278: 7413-7421Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, R. C. G. Mock M. Montecucco C. 1999; PubMed Scopus Google Scholar, 2006; PubMed Scopus Google Scholar). mechanism for activation in the of LeTx or activity in cells Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). However, found that LeTx induces reduction of Bnip3 and Bnip3L mRNA by both and of these resistance to The Mek1 N-terminal and of with the of of of and was by which is that of Mek1 at However, the and to activation in cells of and was further to LeTx We further confirmed that the of was to LeTx-induced down-regulation of Mek1 or but to the activity of LF and inhibitors for found that p38 inhibitors SB202190 or but or both Bnip3 and Bnip3L mRNA and conferred resistance Inhibition of p38 Bnip3 and Bnip3L mRNA Bnip3L activity The role of p38 in the of mRNA stability of a of AU-rich can in including and of as and G. J. Cell. 2004; 16: PubMed Scopus Google Scholar). LeTx mRNA through in the S. E.M. A. J. Cell. Microbiol. 2006; 8: PubMed Scopus Google Scholar). that destabilization of Bnip3 and Bnip3L mRNAs was through of p38 is in to as of mRNAs in with K.S. J. Res. 2005; PubMed Scopus Google Scholar). of Bnip3 and Bnip3L two and G. R. Cell. Full Text PDF PubMed Scopus Google Scholar), a of mRNA stability by Although p38 inhibitors the mRNA as as LeTx, the of mRNA down-regulation by p38 inhibitors at the the by LeTx and that a pathway further Bnip3 and Bnip3L mRNA in In Bnip3L activity was in but in cells The LeTx resistance in a small population of RAW246.7 macrophages to the of p38 and destabilization of Bnip3 and Bnip3L mRNAs Mek1 and of or p38 Down-regulation of these in the LeTx resistance clone is likely to through of Bnip3 and Bnip3L in including for factor, and A.S. Y. K.M. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, S.G. H. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). In the Bnip3 and Bnip3L to by Bnip3 is whereas Bnip3L is through A.S. Y. K.M. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). Bnip3 was also to by in the J. M. N. D. Res. 2006; PubMed Scopus Google Scholar). In macrophages, is in the of factor J. M. Young H.A. E. K. U. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). LeTx resistance cells or activity further macrophages, macrophages resistant to LeTx and of Bnip3 and Bnip3L In macrophages with from cells in that both cells of and Bnip3L in and of macrophages and a mechanism in Bnip3 and Bnip3L to the mechanism for the activation of Bnip3 and Bnip3L and molecular mechanism of Bnip3 and Bnip3L of mitochondrial and cell death are Bnip3 and Bnip3L N-terminal a and G. J. C. G. J. L. D. A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, S. S. M. Y. A. Y. 1999; PubMed Scopus Google Scholar). of by and mediates of of G. J. C. G. J. L. D. A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). is N-terminal of Bnip3 by is a for mitochondrial LeTx induces a rapid reduction in before cell death in macrophages, whereas cells of Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar), that LeTx activity in a rapid of Bnip3 by induces mitochondrial in activity in cells also contribute to the resistance through the Bnip3 and Bnip3L inhibitors also to macrophages from LeTx-induced G. Leppla S.H. Infect. Immun. 1999; PubMed Google Scholar). The and of Bnip3 and Bnip3L are for mitochondrial or and cell of Bnip3 is for cell death of for at within the but cell death A. 2006; 8: PubMed Scopus Google Scholar). proteins, the can for the cell death activity of Bnip3 and Bnip3L S. S. M. Y. A. Y. 1999; PubMed Scopus Google Scholar). In Bnip3 by is with and cell but by of Bnip3 and with with mitochondrial and cell death A. 2006; 8: PubMed Scopus Google Scholar). macrophages and and macrophages from of Bnip3 and Bnip3L either by or LeTx induces in cells or of Bnip3 and Bnip3L through a protein to Macrophages are phagocytes that in and are a crucial of innate LeTx in A. J. Cell. Microbiol. 2005; 7: PubMed Scopus Google Scholar), of Infect. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), and cell death in macrophages, which can contribute to survival of vegetative bacteria and LeTx toxemia J. D. Infect. 2004; PubMed Scopus Google Scholar, P.C. D. R.J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, Y. M. Anderson C. Am. J. Pathol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). and macrophages through the release of LeTx for survival and of B. anthracis within the for anthrax on However, the of after the of J.A. C. M. M. T.L. S. M. J. W.J. 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