Signaling by the Toll-Like Receptors Induces Autophagy Through Modification of Beclin 1: Molecular Mechanism

The innate immune system employs germline-encoded pattern recognition receptors (PRRs) that can detect pathogens and initiate the immune response. The Toll-like receptors (TLRs) are the best studied PRRs and they act by initiating an intracellular signaling cascade that is dependent on the adaptor proteins MyD88 and TRIF. This response activates the critical transcription factors NF-κB and IRF3, and functions to prime both the innate and adaptive immune effector cells for pathogen clearance. Macrophages are one of the major effector cell types of innate immunity. They help clear extracellular infections by phagocytosis and eventual phagosome–lysosome fusion, and intracellular infections by enclosing microbes in autophagic vesicles for delivery to the lysosome. Initiation of autophagy requires phosphatidylinositol 3-phosphate [PtdIns(3)P], which is generated by the phosphatidylinositol 3-kinase class III (PtdIns3KC3/Vps34) complex. This chapter discusses the detailed molecular mechanisms through which TLR signaling primes macrophages for intracellular pathogen clearance by initiating autophagy. We focus on Beclin 1, a key component of the PtdIsn3KC3 complex, which is recruited to the TLR signalosome upon TLR stimulation and subsequently posttranslationally modified to disrupt its binding with its inhibitor, Bcl-2.