anthrax edema toxin modulates pka- and creb-dependent signaling in two phases炭疽水肿毒素调节pka - creb-dependent信号在两个阶段.pdf

Anthrax Edema Toxin Modulates PKA- and CREB- Dependent Signaling in Two Phases 1¤ 1 ´ 1 2 1 Andrea Puhar *, Federica Dal Molin , Stephanie Horvath , Daniel Ladants , Cesare Montecucco * ` ´ ´ 1 Dipartimento di Scienze Biomediche Sperimentali, Universita di Padova, Padova, Italy, 2 Unite de Biochimie des Interactions Macromoleculaires, CNRS URA 2185, Institut Pasteur, Paris, France Abstract Background: Anthrax edema toxin (EdTx) is an adenylate cyclase which operates in the perinuclear region of host cells. However, the action of EdTx is poorly understood, especially at molecular level. The ability of EdTx to modulate cAMP- dependent signaling was studied in Jurkat T cells and was compared with that of other cAMP-rising agents: Bordetella pertussis adenylate cyclase toxin, cholera toxin and forskolin. Methodology/Principal Findings: EdTx caused a prolonged increase of the intracellular cAMP concentration. This led to nuclear translocation of the cAMP-dependent protein kinase (PKA) catalytic subunit, phosphorylation of cAMP response element binding protein (CREB) and expression of a reporter gene under control of the cAMP response element. Neither p90 ribosomal S6 kinase nor mitogen- and stress-activated kinase, which mediate CREB phosphorylation during T cell activation, were involved. The duration of phospho-CREB binding to chromatin correlated with the spatio-temporal rise of cAMP levels. Strikingly, EdTx pre-treated T cells were unresponsive to other stimuli involving CREB phosphorylation such as addition of forskolin