Subversion of RAB5-regulated autophagy by the intracellular pathogen Ehrlichia chaffeensis

Abstract

Intracellular pathogens often exploit RAB functions to establish a safe haven in which to survive and proliferate. Ehrlichia chaffeensis, an obligatory intracellular bacterium, resides in specialized membrane-bound inclusions that have early endosome-like characteristics, e.g., resident RAB5 GTPase and RAB5 effectors, including VPS34 (the catalytic subunit of class III phosphatidylinositol 3-kinase), but the inclusions lack late endosomal or lysosomal markers. Within inclusions, Ehrlichia obtains host-derived nutrients by inducing RAB5-regulated autophagy using Ehrlichia translocated factor-1 deployed by its type IV secretion system. This manipulation of RAB5 by a bacterial molecule offers a simple strategy for Ehrlichia to avoid destruction in lysosomes and obtain nutrients, membrane components, and a homeostatic intra-host-cell environment in which to grow.

Keywords: BECN1; Etf-1; RAB5; autophagy; class III PtdIns3K; endosome; infection; obligatory intracellular; type IV secretion.

Figure 1.

Proposed model for Etf-1-mediated autophagy fueling E. chaffeensis growth. Secreted Etf-1 interacts with RAB5, VPS34, and Beclin 1 to induce complex formation and localize to the ATG5-positive “precursor of preautophagosomes.” If not fused with E. chaffeensis inclusions, Etf-1 autophagosomes mature to autolysosomes to generate cytosolic nutrients (∘∘) (right side). When nascent Etf-1 preautophagosomes fuse with E. chaffeensis inclusions, they deliver captured cytosolic nutrients to the inclusions where lysosomal fusion is blocked (left side).