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

Autophagy is an essential and highly regulated eukaryotic cellular homeostatic process that sequesters and digests/ recycles intracellular components. [12] [13] [14] Multiple membrane sources (plasma membrane, ER/endoplasmic reticulum, mitochondria, endosomes, Golgi) and regulatory factors are involved in the process of autophagy to recognize various cargos and activate downstream components of various pathways (reviewed in ref. 15) . A number of ATG (autophagy-related) proteins regulate autophagosome biogenesis and maturation (reviewed in refs. 15, 16) . In the canonical amino acid starvation-induced pathway in mammalian cells, autophagosome formation is induced by activation of class III PtdIns3K, and an essential component of the PtdIns3K complex, BECN1 (Beclin 1; mammalian ortholog of yeast Vps30/Atg6). 17 ATG12, a ubiquitin-like protein that covalently modifies ATG5, and MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3; a mammalian ortholog family of yeast Atg8) are involved in elongation and expansion of autophagosomes. 18, 19 Biochemical and morphological studies have shown that autophagosomes can fuse with early or late endosomes, forming the amphisome, a hybrid organelle, [20] [21] [22] [23] [24] although detailed mechanisms of these processes remain, for the most part, unknown. Autophagosomes or amphisomes subsequently fuse with lysosomes to form autolysosomes, where captured substrates are degraded and catabolites are released to the cytosol. 15, 25, 26 Autophagy is an important innate immune response against intracellular infections by bacteria such as Salmonella, Shigella, Listeria, and Mycobacterium. [27] [28] [29] [30] [31] In contrast, other intracellular bacteria such as Brucella, Francisella, and Coxiella benefit from autophagy. [32] [33] [34] Brucella abortus-containing double-membrane-enveloped autophagosome formation requires the autophagy initiation proteins ULK1 (unc-51 like autophagy activating kinase 1), BECN1, ATG14, and the class III PtdIns3K, but is independent of ATG5, ATG16L1, ATG4B, ATG7, and MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 b). 33 In addition, autophagosomes are not required for Brucella replication but are required to complete the intracellular Brucella lifecycle and for cell-to-cell spreading. 33 In contrast, Francisella tularensis scavenges intracellular nutrients via ATG5-and LC3-independent noncanonical autophagy. 34 Most bacterial factors that induce autophagy for the benefit of bacteria remain unknown.