MyD88 and Trif Target Beclin 1 to Trigger Autophagy in Macrophages

Abstract

The Toll-like receptors (TLR) play an instructive role in innate and adaptive immunity by recognizing specific molecular patterns from pathogens. Autophagy removes intracellular pathogens and participates in antigen presentation. Here, we demonstrate that not only TLR4, but also other TLR family members induce autophagy in macrophages, which is inhibited by MyD88, Trif, or Beclin 1 shRNA expression. MyD88 and Trif co-immunoprecipitate with Beclin 1, a key factor in autophagosome formation. TLR signaling enhances the interaction of MyD88 and Trif with Beclin 1, and reduces the binding of Beclin 1 to Bcl-2. These findings indicate TLR signaling via its adaptor proteins reduces the binding of Beclin 1 to Bcl-2 by recruiting Beclin 1 into the TLR-signaling complex leading to autophagy.One of the mechanisms by which the innate immune system senses the invasion of pathogenic microorganisms is through Toll-like receptors (TLRs), 3 which recognize specific molecular patterns that are present in microbial components. Stimulation of different TLRs induces distinct patterns of gene expression, which not only leads to the activation of innate immunity, but also instructs the development of antigen-specific acquired immunity (1, 2). TLR signaling predominantly induces interferon regulatory factors, and nuclear factor-B (NF-B) and AP1 activation. This elicits the production of type I interferon and inflammatory cytokines (3, 4). TLR signaling also facilitates the selection of microbial antigens for presentation by dendritic cells (5). Parasitic protozoans can also trigger TLRs enhancing resistance to them by triggering pro-inflammatory responses (6). Ten members of the TLR family have been identified in human, and 13 in mice (4). Signaling by TLRs involves five adaptor proteins known as MyD88, MyD88-adapter like (MAL), Toll/interleukin receptor (TIR) domain-containing adaptor protein inducing interferon ␤ (TRIF), TRIF-related adaptor molecule (TRAM), and sterile ␣-and armadillo motifcontaining protein (SARM). MAL recruits MyD88 to TLR2 and TLR4, and TRAM recruits TRIF to TLR4 to allow interferon regulator factor 3 activation. SARM negatively regulates TRIF. MyD88 is the key signaling adaptor for all TLRs with the exception of TLR3 and a subset of TLR4 signals, which utilize Trif (7).Autophagy is a cellular response to starvation as well as a quality control system that can remove damaged organelles and long-lived proteins from cytoplasm. Autophagy plays a role in programmed cell death, the promotion and prevention of cancer, neurodegeneration, and cellular defense to remove invading pathogens (8). Recently, it has been recognized that autophagy is involved in both innate and adaptive immunity against intracellular protozoa, bacteria, and viruses (9 -11). Autophagy has been implicated in major histocompatibility complex class II antigen presentation. During autophagy cytoplasmic materials are sequestered into double membrane-coated autophagosomes, which fuse with endosomes and lysosomes to form autolysosomes where the contents...

Loss of autophagy enhances MIF/macrophage migration inhibitory factor release by macrophages

“…Previous studies have demonstrated that both IL1A and IL1B induce autophagy in macrophages, which in turn limits their secretion. 15,17,38 This would suggest a bidirectional feedback mechanism for release of these pro-inflammatory cytokines. A role for MIF in promoting or inhibiting the autophagy-dependent regulation of IL1A and IL1B would be a novel and important finding in the context of inflammation.…”

Poxviral Protein A46 Antagonizes Toll-like Receptor 4 Signaling by Targeting BB Loop Motifs in Toll-IL-1 Receptor Adaptor Proteins to Disrupt Receptor:Adaptor Interactions

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Extracellular stimulation of VSIG4/complement receptor Ig suppresses intracellular bacterial infection by inducing autophagy

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