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TLR4 Signaling Regulates Lysosome Exocytosis to a Novel Extracellular Compartment
Author(s) -
Singh Rajesh K,
Haka Abigail S,
Chin Harvey F,
Grosheva Inna,
Maxfield Frederick R
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.591.3
Subject(s) - microbiology and biotechnology , lysosome , exocytosis , endocytic cycle , endocytosis , protein kinase b , pi3k/akt/mtor pathway , signal transduction , chemistry , biology , biochemistry , secretion , receptor , enzyme
We have characterized a novel form of endocytosis in which macrophages use lysosome exocytosis to degrade large species, such as aggregated lipoproteins. Exocytosis is targeted to an extracellular, acidic, hydrolytic compartment (a lysosomal synapse) and its formation is dependent on TLR4 and its adaptor MyD88. Macrophage degradation of aggregated lipoproteins using the lysosomal synapse transforms them into foam cells, a key pathological feature of atherosclerotic plaques. Compartment formation is characterized by local actin polymerization, targeted secretion of lysosomal contents and generation of an acidic environment. These activities require carefully coordinated signal transduction processes. Using macrophages from knockout mice, siRNA silencing or pharmacological inhibitors, data identify phosphoinositide 3‐kinase, phosphoinositide‐dependent kinase 1, protein kinase B (Akt), Bruton's tyrosine kinase, phospholipase C, protein kinase C, soluble NSF attachment receptor (SNARE) proteins and calcium mobilization as important components downstream of TLR4/MyD88 leading to lysosome exocytosis to the lysosomal synapse. Efforts are currently underway to examine the relevance of this pathway to several other diseases, such as Alzheimer's, diabetes and cancer.