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

Taken together, several aspects are unusual in this form of pathogen effector-induced autophagy: 1) autophagy induction is essential for bacterial replication, as it provides nutrients to intracellular bacteria; 2) autophagosomes form proximally to inclusions, but their maturation is arrested, so autophagy cannot function as an innate immune mechanism to clear the infection; 3) a T4S effector interacts with autophagy proteins to induce autophagosome formation and homes to the bacterial inclusions; and 4) canonical starvation-induced MTOR inhibition and ULK activation are not involved. Although this is similar to A. phagocytophilum Ats-1-induced autophagy, 37 there are clear differences between the 2 bacteria: 1) RAB5 is involved in E. chaffeensis-induced autophagy, but not in A. phagocytophilum-induced autophagy; 2) Etf-1 and Ats-1 promote distinct autophagy nucleation complexes derived from early endosomes and ER, respectively; 3) E. chaffeensis inclusions appear as early amphisomes without LC3-II localization, whereas A. phagocytophilum inclusions are early autophagosomes with distinct LC3-II localization; 37 and 4) Etf-1 and Ats-1, despite their 21% amino acid sequence identity, selectively target and promote E. chaffeensis and A. phagocytophilum growth, 37 respectively. How the 2 molecules recruit distinct autophagy membrane precursors and recognize the parent bacterial inclusions remains to be studied.