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Trafficking-Mediated STING Degradation Requires Sorting to Acidified
Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response
#MMPMID29241549
Gonugunta VK
; Sakai T
; Pokatayev V
; Yang K
; Wu J
; Dobbs N
; Yan N
Cell Rep
2017[Dec]; 21
(11
): 3234-3242
PMID29241549
show ga
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.
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