Bacterial serine/threonine protein kinases in host-pathogen interactions

Abstract

In bacterial pathogenesis, monitoring and adapting to the dynamically changing environment in the host and an ability to disrupt host immune responses are critical. The virulence determinants of pathogenic bacteria include the sensor/signaling proteins of the serine/threonine protein kinase (STPK) family that have a dual role of sensing the environment and subverting specific host defense processes. STPKs can sense a wide range of signals and coordinate multiple cellular processes to mount an appropriate response. Here, we review some of the well studied bacterial STPKs that are essential virulence factors and that modify global host responses during infection.

Keywords: Bacterial Signal Transduction; Host-Pathogen Interactions; Protein Secretion; Serine/Threonine Protein Kinase; Virulence Factors.

FIGURE 1.

Y. pestis YpkA phosphorylates a host substrate and interferes with the host RhoA/Rac pathway. A, YpkA is a multidomain protein harboring an STPK domain, a GDI domain, and an actin-binding domain (ABD). aa, amino acids. B, in an inactive form, the heterotrimeric G-protein Gα_q-βγ is associated with G-protein-coupled receptors (R), with Gα_q bound to GDP. Upon activation of the receptor, GDP is exchanged for GTP on Gα_q, which induces dissociation of the trimer from the receptor, and into Gα_q and Gβγ subunits. Gα_q-GTP activates the RhoA/Rac pathway through the LARG Rho guanine nucleotide exchange factor (leukemia-associated RhoGEF), which triggers formation of actin stress fibers. The GTPase activity of Gα_q then hydrolyzes GTP to GDP, and the system reverts to the inactivate state. C, when YpkA is secreted into the host cell, its STPK domain is activated through interaction with host actin, and it phosphorylates Gα_q. The latter can no longer bind GTP, which eventually leads to disruption of cytoskeletal integrity. Concurrently, the GDI domain of YpkA interacts with RhoA and Rac, leading to a switch off of the RhoA/Rac pathways.

FIGURE 2.

Interference with the host NF-κB signaling pathways by STPKs of pathogenic bacteria: LegK1, OspG, and NleH1. In the canonical NF-κB pathway, in response to stimulation, the IKK trimer (IKKα/IKKβ/NEMO) phosphorylates IκB inhibitor (here, IκBα), which normally sequesters the NF-κB (p50/p65) dimer in the cytoplasm. Once phosphorylated, IκBα dissociates from NF-κB dimer, which then translocates into the nucleus and activates genes implicated in the immune response. The dissociated phospho-IκBα is ubiquitinated by the ubiquitinylation system (E1, E2, and E3) and is addressed to and degraded in the proteasome. In the non-canonical pathway, the IKKα dimer phosphorylates p100, the precursor of p52 that is an inhibitor of the NF-κB dimer. Once phosphorylated, p100 is processed to p52, and the p52/RelB NF-κB dimer thus activated is translocated into the nucleus. The Legionella STPK LegK1 mimics IKKs in both canonical (A, left) and non-canonical (B) pathways and induces activation of the NF-κB pathways in the host. A (right), the Shigella sp. STPK OspG interacts with the ubiquitin-conjugating enzyme E2, blocking phospho-IκBα degradation and thus silencing the inflammatory response of the host. C, the RPS3 protein interacts with the p65 subunit of NF-κB, and when phosphorylated by IKKα, RPS3 is translocated into the nucleus and determines the regulatory specificity of NF-κB for target genes. The E. coli STPK NleH1 inhibits RPS3 phosphorylation and thus inhibits the host NF-κB response mechanism. CRKL could be involved in this inhibition, but the exact mechanism remains to be elucidated.