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

Anthrax is a life threatening disease caused by infection with Bacillus anthracis, 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. We herein report that LT exposure rapidly reduces the levels of cJun, a key regulator of cell proliferation and survival. Blockade of proteasome dependent protein degradation with the 26S proteasome inhibitor MG132 largely restored cJun protein levels, suggesting that LT promotes degradation of cJun protein. Using the MKK1/2 inhibitor U0126, we further show that MKK1/2/Erk1/2 pathway inactivation similarly reduces cJun protein, also restored by MG132 pre-exposure. Interestingly, cJun protein rebounded to normal levels 4 hours following U0126 exposure, but not after LT exposure. The restoration of cJun in U0126 exposed cells was associated with increased cJun mRNA levels and was blocked by inactivation of the JNK1/2 signaling pathway. These results indicate that LT reduces cJun both by promoting cJun protein degradation via inactivation of MKK1/2/Erk1/2 signaling and by blocking cJun gene transcription via inactivation of MKK4/JNK1/2 signaling. In line with cJuns known functions, 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 cJun protein levels and cell proliferation. Taken together, these findings indicate that LT reduces cJun protein levels via two distinct mechanisms, thereby inhibiting critical cell functions, including cellular proliferation.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2feRT12
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