Signaling pathway of autophagy associated with innate immunity.
Autophagy has recently been shown to be an important component of the innate immune response. The signaling pathways leading to activation of autophagy in innate immunity are not well studied. Our recent study shows that Toll-like receptor 4 (TLR 4) serves as an environmental sensor for autophagy. We define a new molecular pathway in which lipopolysaccharide (LPS) induces autophagy in human and murine macrophages by a pathway regulated through Toll-interleukin 1 receptor domain-containing adaptor-inducing interferon-beta (TRIF)-dependent, myeloid differentiation factor 88 (MyD88)-independent TLR4 signaling. Receptor-interacting protein (RIP1) and p38 mitogen-activated protein-kinase (MAPK) are downstream components of this pathway. This signaling pathway does not affect cell viability, indicating that it is distinct from an autophagic death signaling pathway. We further show that LPS-induced autophagy can enhance mycobacterial co-localization with the autophagosomes. The above study raises important questions. (1) What is the complete signaling pathway for LPS-induced autophagy? (2) Does TLR3 mediate autophagy? (3) What are the mechanisms that determine whether autophagy acts as a pro-death or pro-survival pathway? (4) What are the physiological functions of LPS-induced autophagosomes? Future studies examining the above questions should provide us with important clues as to how autophagy is regulated in innate immunity, and how autophagy can be utilized in pathogen clearance.
Xu
Yi
Y
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Liu
Xian-De
XD
Gong
Xing
X
Eissa
N Tony
NT
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D016923:Cell Death; D002470:Cell Survival; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
D033942:Adaptor Proteins, Vesicular Transport; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases