Ehrlichia secretes Etf-1 to induce autophagy and capture nutrients for its growth through RAB5 and class III phosphatidylinositol 3-kinase

Lin, Mingqun; Liu, Hongyan; Xiong, Qingming; Niu, Hua; Cheng, Zhihui; Yamamoto, Akitsugu; Rikihisa, Yasuko

RAB GTPases are the central regulators of membrane trafficking and organellar identity in eukaryotic cells. 104 RAB5 is found in nascent phagosomes and early endosomes that lack the microbicidal capacity required to kill invading pathogens; this requires subsequent maturation into late endosomes via the transition from RAB5 to RAB7 and lysosomal fusion. Consequently several intracellular pathogens prevent or delay the RAB5 to RAB7 transition. For example, M. tuberculosis localizes in the RAB5-positive endocytic compartment by reducing PtdIns3P in the phagosomal membrane, thereby interfering with phagosome maturation. 109, 110 Listeria monocytogenes GAPDH binds and carries out ADP-ribosylation of RAB5A and impairs the GDP/GTP exchange and thereby blocks phagosome maturation. 111 Maturation arrest of RAB5-positive E. chaffeensis inclusions is distinct from these examples, as PtdIns3P is highly enriched and the blockade seems to be due to RAB5 GTPase inactivation, based on the ability of SGSM3 overexpression to overcome the blockade. In agreement with this observation, the stable presence of the RAB5 effectors EEA1, PIK3C3, and ANKFY1 on E. chaffeensis-containing inclusions and the inhibition of E. chaffeensis infection by overexpression of RAB5-DN or SGSM3 suggest that RAB5 is mostly locked in the GTP-bound state on E. chaffeensis inclusions.