Open AccessC oxiella burnetii exploits host cAMP ‐dependent protein kinase signalling to promote macrophage survival
Author(s) -
MacDonald Laura J.,
Graham Joseph G.,
Kurten Richard C.,
Voth Daniel E.
Publication year - 2014
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/cmi.12213
Subject(s) - biology , microbiology and biotechnology , effector , protein kinase a , protein kinase b , kinase , coxiella burnetii , intracellular parasite , secretion , intracellular , signal transduction , biochemistry
Summary Intracellular bacterial pathogens often subvert apoptosis signalling to regulate survival of their host cell, allowing propagation of the bacterial population. C oxiella burnetii , the intracellular agent of human Q fever, inhibits host cell apoptosis through several mechanisms, including prevention of mitochondrial cytochrome c release, triggering of an anti‐apoptotic transcriptional programme, and activation of pro‐survival kinases. To control host cell survival, C . burnetii delivers effector proteins to the eukaryotic cytosol using a specialized Dot / Icm type IV secretion system ( T 4 SS ). Effectors are predicted to regulate activity of pro‐survival host signalling proteins, such as Akt and cAMP ‐dependent protein kinase ( PKA ), to control infection. Here, we show that host PKA activity is required for C . burnetii inhibition of macrophage apoptosis. PKA is activated during infection and inhibits activity of the pro‐apoptotic protein Bad via phosphorylation. Bad is also phosphorylated at an Akt ‐specific residue, indicating C . burnetii uses two kinases to fully inactivate Bad . Additionally, Bad and the tethering protein 14‐3‐3β colocalize at the C . burnetii parasitophorous vacuole ( PV ) membrane during infection, an event predicted to alter Bad promotion of apoptosis. Inhibiting PKA activity prevents Bad recruitment to the PV , but the protein is retained at the membrane during induction of apoptosis. Finally, PKA regulatory subunit I ( RI ) traffics to the PV membrane in a T 4 SS ‐dependent manner, suggesting a C . burnetii effector(s) regulates PKA ‐dependent activities. This study is the first to demonstrate subversion of host PKA activity by an intracellular bacterial pathogen to prevent apoptosis and survive within macrophages.