Anaplasma phagocytophilum induces actin phosphorylation to selectively regulate gene transcription in Ixodes scapularis ticks

J Exp Med. 2010 Aug 2;207(8):1727-43. doi: 10.1084/jem.20100276. Epub 2010 Jul 26.

Abstract

Anaplasma phagocytophilum, the agent of human anaplasmosis, persists in ticks and mammals. We show that A. phagocytophilum induces the phosphorylation of actin in an Ixodes ricinus tick cell line and Ixodes scapularis ticks, to alter the ratio of monomeric/filamentous (G/F) actin. A. phagocytophilum-induced actin phosphorylation was dependent on Ixodes p21-activated kinase (IPAK1)-mediated signaling. A. phagocytophilum stimulated IPAK1 activity via the G protein-coupled receptor Gbetagamma subunits, which mediated phosphoinositide 3-kinase (PI3K) activation. Disruption of Ixodes gbetagamma, pi3k, and pak1 reduced actin phosphorylation and bacterial acquisition by ticks. A. phagocytophilum-induced actin phosphorylation resulted in increased nuclear G actin and phosphorylated actin. The latter, in association with RNA polymerase II (RNAPII), enhanced binding of TATA box-binding protein to RNAPII and selectively promoted expression of salp16, a gene crucial for A. phagocytophilum survival. These data define a mechanism that A. phagocytophilum uses to selectively alter arthropod gene expression for its benefit and suggest new strategies to interfere with the life cycle of this intracellular pathogen, and perhaps other Rickettsia-related microbes of medical importance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / metabolism*
  • Anaplasma phagocytophilum / cytology
  • Anaplasma phagocytophilum / physiology*
  • Animals
  • Cell Line
  • Cell Nucleus / metabolism
  • Enzyme Inhibitors / pharmacology
  • GTP-Binding Protein beta Subunits / genetics
  • GTP-Binding Protein beta Subunits / metabolism
  • GTP-Binding Protein gamma Subunits / genetics
  • GTP-Binding Protein gamma Subunits / metabolism
  • Gastrointestinal Tract / metabolism
  • Gene Expression / genetics
  • Gene Expression Regulation / physiology*
  • Insect Proteins / antagonists & inhibitors
  • Insect Proteins / genetics
  • Insect Proteins / metabolism
  • Ixodes / drug effects
  • Ixodes / metabolism*
  • Ixodes / microbiology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Promoter Regions, Genetic / genetics
  • Protein Binding / physiology
  • RNA Interference
  • RNA Polymerase II / metabolism
  • Salivary Glands / metabolism
  • Salivary Proteins and Peptides / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • TATA-Box Binding Protein / metabolism
  • Transcription, Genetic / genetics
  • p21-Activated Kinases / antagonists & inhibitors
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism

Substances

  • Actins
  • Enzyme Inhibitors
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Insect Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • Salivary Proteins and Peptides
  • Salp15 protein, Ixodes scapularis
  • Salp16 protein, Ixodes scapularis
  • TATA-Box Binding Protein
  • p21-Activated Kinases
  • RNA Polymerase II