Anthrax Lethal Toxin Inhibits Translation of Hypoxia-inducible Factor 1α and Causes Decreased Tolerance to Hypoxic Stress

Ouyang, Wei; Torigoe, Chikako; Fang, Hui; Xie, Tao; Frucht, David M.

doi:10.1074/jbc.m113.530006

Cited by 14 publications

(12 citation statements)

References 56 publications

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“…LF is a zinc-dependent metalloprotease with specific activity against MKKs. Consistent with our previous studies (22,24), LT treatment led to cleavage and degradation of MKK1, MKK2, MKK3, MKK4, and MKK6, but not MKK7, in Hepa1c1c7 cells (Fig. 4A).…”

Section: Lt Treatment Reduces C-jun Protein By Inhibiting the Mkk1/2-supporting

confidence: 93%

“…We have reported previously that LT inhibits the accumulation of hypoxia-inducible factor (HIF) 1␣, the master regulator of cellular responses to hypoxia, by blocking its translation (22). To investigate whether LT inhibits c-Jun by a similar mechanism, we first investigated the effect of LT treatment on de novo c-Jun protein synthesis.…”

Section: Rapid Lt-induced Reduction Of C-jun Does Not Occur At the Lementioning

confidence: 99%

“…Cell extracts were then separated on 4 -12% NuPAGE BisTris gels (Invitrogen) and transferred to nitrocellulose membranes (Bio-Rad). The membranes were probed with antibodies of interest using standard Western blotting techniques as described previously (22).…”

Section: Western Blottingmentioning

confidence: 99%

“…Polysome analysis was performed as described previously (22,57). In brief, HepG2 cells were pretreated with or without LT for 3 h. The treated cells were then incubated with 0.1 mg/ml CHX for 5 min, detached by scraping into 1 ml of polysome extraction buffer (0.3 M NaCl, 15 mM MgCl 2 , 15 mM Tris-HCl (pH 7.6), 1% Triton X-100, 1 mg/ml heparin, and 0.1 mg/ml CHX), and lysed on ice for 10 min.…”

Section: Polysome Analysismentioning

confidence: 99%

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Anthrax lethal toxin rapidly reduces c-Jun levels by inhibiting c-Jun gene transcription and promoting c-Jun protein degradation

Ouyang

Guo

Fang

et al. 2017

Journal of Biological Chemistry

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Anthrax is a life-threatening disease caused by infection with , which expresses lethal factor and the receptor-binding protective antigen. These two proteins combine to form anthrax lethal toxin (LT), whose proximal targets are mitogen-activated kinase kinases (MKKs). However, the downstream mediators of LT toxicity remain elusive. Here we report that LT exposure rapidly reduces the levels of c-Jun, a key regulator of cell proliferation and survival. Blockade of proteasome-dependent protein degradation with the 26S proteasome inhibitor MG132 largely restored c-Jun protein levels, suggesting that LT promotes degradation of c-Jun protein. Using the MKK1/2 inhibitor U0126, we further show that MKK1/2-Erk1/2 pathway inactivation similarly reduces c-Jun protein, which was also restored by MG132 pre-exposure. Interestingly, c-Jun protein rebounded to normal levels 4 h following U0126 exposure but not after LT exposure. The restoration of c-Jun in U0126-exposed cells was associated with increased c-Jun mRNA levels and was blocked by inactivation of the JNK1/2 signaling pathway. These results indicate that LT reduces c-Jun both by promoting c-Jun protein degradation via inactivation of MKK1/2-Erk1/2 signaling and by blocking c-Jun gene transcription via inactivation of MKK4-JNK1/2 signaling. In line with the known functions of c-Jun, LT also inhibited cell proliferation. Ectopic expression of LT-resistant MKK2 and MKK4 variants partially restored Erk1/2 and JNK1/2 signaling in LT-exposed cells, enabling the cells to maintain relatively normal c-Jun protein levels and cell proliferation. Taken together, these findings indicate that LT reduces c-Jun protein levels via two distinct mechanisms, thereby inhibiting critical cell functions, including cellular proliferation.

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Section: Lt Treatment Reduces C-jun Protein By Inhibiting the Mkk1/2-supporting

confidence: 93%

Section: Rapid Lt-induced Reduction Of C-jun Does Not Occur At the Lementioning

confidence: 99%

Section: Western Blottingmentioning

confidence: 99%

Section: Polysome Analysismentioning

confidence: 99%

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Anthrax lethal toxin rapidly reduces c-Jun levels by inhibiting c-Jun gene transcription and promoting c-Jun protein degradation

Ouyang

Guo

Fang

et al. 2017

Journal of Biological Chemistry

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“…The changes in active translational factors causes decreased translation of Hypoxia-Induced Factor-1a (HIF1 a), a central protein involved in the host cell response against hypoxic condition. Severely decreased expression of HIF-1a could lead to pathological conditions in host like angiogenesis and metastasis [50]. The implications of N-terminus cleavage of MAPKK family members have been found to be diverse.…”

Section: Lethal Toxinmentioning

confidence: 99%

Bacterial Virulence Factors: Secreted for Survival

et al. 2016

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Virulence is described as an ability of an organism to infect the host and cause a disease. Virulence factors are the molecules that assist the bacterium colonize the host at the cellular level. These factors are either secretory, membrane associated or cytosolic in nature. The cytosolic factors facilitate the bacterium to undergo quick adaptive-metabolic, physiological and morphological shifts. The membrane associated virulence factors aid the bacterium in adhesion and evasion of the host cell. The secretory factors are important components of bacterial armoury which help the bacterium wade through the innate and adaptive immune response mounted within the host. In extracellular pathogens, the secretory virulence factors act synergistically to kill the host cells. In this review, we revisit the role of some of the secreted virulence factors of two human pathogens: Mycobacterium tuberculosis-an intracellular pathogen and Bacillus anthracis-an extracellular pathogen. The advances in research on the role of secretory factors of these pathogens during infection are discussed.

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Bacillus anthracis Toxins: Efficient Biochemical Weapons for the Infectious Battle

Trescos¹,

Rougeaux²,

Tournier³

2018

Toxinology

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Anthrax Lethal Toxin Inhibits Translation of Hypoxia-inducible Factor 1α and Causes Decreased Tolerance to Hypoxic Stress

Cited by 14 publications

References 56 publications

Anthrax lethal toxin rapidly reduces c-Jun levels by inhibiting c-Jun gene transcription and promoting c-Jun protein degradation

Anthrax lethal toxin rapidly reduces c-Jun levels by inhibiting c-Jun gene transcription and promoting c-Jun protein degradation

Bacterial Virulence Factors: Secreted for Survival

Bacillus anthracis Toxins: Efficient Biochemical Weapons for the Infectious Battle

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