Bacillus bombysepticus α-Toxin Binding to G Protein-Coupled Receptor Kinase 2 Regulates cAMP/PKA Signaling Pathway to Induce Host Death

Abstract

Bacterial pathogens and their toxins target host receptors, leading to aberrant behavior or host death by changing signaling events through subversion of host intracellular cAMP level. This is an efficient and widespread mechanism of microbial pathogenesis. Previous studies describe toxins that increase cAMP in host cells, resulting in death through G protein-coupled receptor (GPCR) signaling pathways by influencing adenylyl cyclase or G protein activity. G protein-coupled receptor kinase 2 (GRK2) has a central role in regulation of GPCR desensitization. However, little information is available about the pathogenic mechanisms of toxins associated with GRK2. Here, we reported a new bacterial toxin-Bacillus bombysepticus (Bb) α-toxin that was lethal to host. We showed that Bb α-toxin interacted with BmGRK2. The data demonstrated that Bb α-toxin directly bound to BmGRK2 to promote death by affecting GPCR signaling pathways. This mechanism involved stimulation of Gαs, increase level of cAMP and activation of protein kinase A (PKA). Activated cAMP/PKA signal transduction altered downstream effectors that affected homeostasis and fundamental biological processes, disturbing the structural and functional integrity of cells, resulting in death. Preventing cAMP/PKA signaling transduction by inhibitions (NF449 or H-89) substantially reduced the pathogenicity of Bb α-toxin. The discovery of a toxin-induced host death specifically linked to GRK2 mediated signaling pathway suggested a new model for bacterial toxin action. Characterization of host genes whose expression and function are regulated by Bb α-toxin and GRK2 will offer a deeper understanding of the pathogenesis of infectious diseases caused by pathogens that elevate cAMP.

G-Protein Coupled Receptors (GPCRs): Signaling Pathways, Characterization, and Functions in Insect Physiology and Toxicology

“…A great deal of work is being done to characterize these hypothetical pathways and GPCR downstream effectors in insects [ 27 , 34 , 118 , 119 , 120 , 121 ]. Studies have revealed specific GPCR genes and their potential biological functions that may impact insects’ physiology [ 21 , 22 ], including their reproduction [ 23 , 24 , 25 , 26 , 27 , 28 ], and regulating their growth and development [ 27 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ], as well as their stress responses [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ], their feeding patterns [ 27 , 32 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ], their other behaviors [ 23 , 61 , 62 ,…”

Annexin A2 positively regulates milk synthesis and proliferation of bovine mammary epithelial cells through the mTOR signaling pathway

“…As one of the key environmental stimuli, amino acids can be sensed by G protein coupled receptor (GPCR) (Fujiwara et al, ; Wauson, Zaganjor, & Cobb, ). Previous reports have shown that GPCRs can activate PKC (Cattaneo, Parisi & Ammendola, ) and PKA (Lin et al, ), which two can phosphorylate AnxA2. And some GPCRs can regulate the levels of matrix metalloproteinase 2 (MMP2) and MMP9 of protease (Liu et al, ).…”

Role of a serine protease gene (AccSp1) from Apis cerana cerana in abiotic stress responses and innate immunity

“…Different letters above the bars indicate significant differences (p < 0.05) according to the SAS software activation of PKA, etc. that induced host death (Lin et al 2016). In our study, we found that the survival rate of bees was high, approximately 70% when they were injected only with dsSp1, compared with the survival rate of dsSp1-treated adults injected with Bb that was significantly decreased to approximately 10-20% ( Fig.…”