Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response

Vijay K. Gonugunta, Tomomi Sakai, Vladislav Pokatayev, Kun Yang, Jianjun Wu, Nicole Dobbs, Nan Yan

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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. STING activation turns on and quickly turns off downstream signaling as it moves through the secretory pathway. Gonugunta et al. found that trafficking-mediated STING degradation requires ER exit and sorting of STING vesicles to lysosomes for degradation. Blockade of STING degradation enhances STING signaling and anti-tumor response.

Original languageEnglish (US)
Pages (from-to)3234-3242
Number of pages9
JournalCell Reports
Volume21
Issue number11
DOIs
StatePublished - Dec 12 2017

Fingerprint

Sorting
Endoplasmic Reticulum
Tumors
Degradation
Lysosomes
Neoplasms
Vacuolar Proton-Translocating ATPases
Immunoelectron Microscopy
Secretory Pathway
Cyclic GMP
Adenosine Monophosphate
Cluster Analysis
Amino Acids
Therapeutics
Electron microscopy
Proteins
Chemical activation
Topology
Imaging techniques

Keywords

  • anti-tumor response
  • lysosomes
  • STING degradation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response. / Gonugunta, Vijay K.; Sakai, Tomomi; Pokatayev, Vladislav; Yang, Kun; Wu, Jianjun; Dobbs, Nicole; Yan, Nan.

In: Cell Reports, Vol. 21, No. 11, 12.12.2017, p. 3234-3242.

Research output: Contribution to journalArticle

Gonugunta, Vijay K. ; Sakai, Tomomi ; Pokatayev, Vladislav ; Yang, Kun ; Wu, Jianjun ; Dobbs, Nicole ; Yan, Nan. / Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response. In: Cell Reports. 2017 ; Vol. 21, No. 11. pp. 3234-3242.
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