Trafficking-mediated STING degradation requires sorting to acidified endolysosomes and can be therapeutically targeted to enhance anti-tumor response
Autor: | Gonugunta, Vijay K, Sakai, Tomomi, Pokatayev, Vladislav, Yang, Kun, Wu, Jianjun, Dobbs, Nicole, Yan, Nan |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
Lipopolysaccharides
Mice Knockout Models Molecular Melanoma Experimental Gene Expression Membrane Proteins rab7 GTP-Binding Proteins Endosomes Endoplasmic Reticulum eye diseases Article Protein Structure Secondary Tumor Burden Mice Inbred C57BL Mice Protein Transport Poly I-C rab GTP-Binding Proteins Proteolysis Animals Humans Macrolides Nucleotides Cyclic Lysosomes Signal Transduction |
Popis: | STING is an endoplasmic reticulum (ER)-associated transmembrane protein that turns on and quickly turns off downstream signaling as it translocates from the ER to vesicles. How STING signaling is attenuated during trafficking remains poorly understood. Here, we show that trafficking-mediated STING degradation requires ER exit and function of vacuolar ATPase complex. Late-stage STING vesicles are sorted to Rab7-positive endolysosomes for degradation. Based on analysis of existing structures, we also identified the helix amino acid 281 (aa281)-297 as a motif required for trafficking-mediated STING degradation. Immuno-electron microscopy (EM) reveals the size and clustering of STING vesicles and topology of STING on the vesicle. Importantly, blockade of trafficking-mediated STING degradation using bafilomycin A1 specifically enhanced cyclic guanosine monophosphate (GMP)-AMP (cGAMP)-mediated immune response and anti-tumor effect in mice. Together, our findings provide biochemical and imaging evidence for STING degradation by the lysosome and pinpoint trafficking-mediated STING degradation as a previously unanticipated therapeutic target for enhancing STING signaling in cancer therapy. |
Databáze: | OpenAIRE |
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