Activation of the @entity2308 -NF-kappaB pathway by subtilase cytotoxin through the XXXX branch of the unfolded protein response.

@entity2308 @entity12381 @entity21205 @entity37735 @entity526 @entity73082
Shiga toxin has the potential to induce expression of inflammation-associated genes, although the underlying mechanisms are not well understood. We examined the effects of subtilase cytotoxin (SubAB), an AB(5) toxin produced by some Shiga toxigenic @entity526 , on the activation of NF-kappaB. SubAB is known to be a protease which selectively degrades @entity21205 / @entity21205 . Treatment of NRK-52E cells with SubAB caused rapid cleavage of @entity21205 . Following the degradation of @entity21205 , transient activation of NF-kappaB was observed with a peak at 6-12 h; the activation subsided within 24 h despite the continuous absence of intact @entity21205 . The activation of NF-kappaB was preceded by transient phosphorylation of @entity2308 . Treatment of the cells with a selective inhibitor of @entity73082 or an inhibitor of PI3K attenuated SubAB-induced NF-kappaB activation, suggesting that activation of @entity2308 is an event upstream of NF-kappaB. Degradation of @entity21205 caused the unfolded protein response (UPR), and inducers of the UPR mimicked the stimulatory effects of SubAB on @entity2308 and NF-kappaB. SubAB triggered the three major branches of the UPR including the IRE1- @entity12381 , PERK, and @entity37735 pathways. Dominant-negative inhibition of IRE1alpha, @entity12381 , or PERK did not attenuate activation of NF-kappaB by SubAB. In contrast, genetic and pharmacological inhibition of @entity37735 significantly suppressed SubAB-triggered @entity2308 phosphorylation and NF-kappaB activation. These results suggested that loss of @entity21205 by SubAB leads to transient phosphorylation of @entity2308 and consequent activation of NF-kappaB through the @entity37735 branch of the UPR.
