# An effector of phosphatidylinositol 3-kinase activity promotes Rickettsia rickettsii virulence by enhancing autophagy

## TL;DR

The study shows how a protein from Rickettsia rickettsii boosts its virulence by increasing autophagy through a lipid signaling pathway.

## Contribution

The paper identifies PikA as a bacterial phosphatidylinositol 3-kinase that promotes virulence by inducing autophagy.

## Key findings

- PikA converts phosphatidylinositol into PI3P, promoting autophagosome formation via interaction with Beclin 1.
- Myotubularin suppresses PikA's effects and inhibits R. rickettsii replication.
- Modulation of PI metabolism by PikA is critical for R. rickettsii virulence.

## Abstract

To establish an intracellular niche conductive to growth, some bacterial pathogens deliver virulence factors that modulate phosphoinositides (PIPs) metabolism. PIPs are a family of lipids involved in signaling that regulates key cellular processes. Rickettsia rickettsii, the etiological agent of Rocky Mountain spotted fever, codes for a type IV secretion system (T4SS), but the mechanism by which its secreted substrates contribute to virulence remains largely unclear. Here, we found that the T4SS effector PikA of R. rickettsii is a phosphatidylinositol 3-kinase (PI3K) that converts phosphatidylinositol (PI) into phosphatidylinositol 3-phosphate (PI3P). This conversion leads to PI3P accumulation at phagophore assembly sites, promoting autophagosome formation through kinase activity-dependent interaction with Beclin 1. The effects of PikA can be suppressed by the PI3P-specific phosphatase Myotubularin. Furthermore, the expression of Myotubularin suppressed intracellular R. rickettsii replication, indicating that autophagy induced by elevated PI3P is beneficial for bacterial virulence. Our findings establish that PikA modulates host PI metabolism via its PI3K activity to promote R. rickettsii intracellular growth by inducing autophagy.

The phosphatidylinositol derivative PI3P is a key second messenger that regulates multiple cellular processes, particularly membrane trafficking and autophagy. We report here that PikA, a T4SS substrate of R. rickettsii, functions as a PI-3 kinase that catalyzes the production of PI3P to promote autophagy influx. PikA achieves this by recruiting Beclin 1 through direct protein-protein interactions. The expression of the dual-specific PI phosphatase Myotubularin counteracted the effects of PikA and inhibited intracellular R. rickettsii replication. Our results reveal that the modulation of PI metabolism by a bacterial PI-3 kinase is critical for R. rickettsii virulence, and this pathway may provide potential target for the development of therapeutics against infections caused by this pathogen.