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

doi:10.1016/j.celrep.2017.11.061

Cited by 219 publications

(243 citation statements)

References 22 publications

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“…Of the non-kinase inhibitors, we were intrigued by both bafilomycin and concanomycin, which blocked pathway activation at low doses, but unexpectedly potentiated pathway activity at higher doses. We did not delve into this further, but note that a recent report (27) implicated a negative regulatory role of ATP6V1A, consistent with our finding.…”

Section: Resultssupporting

confidence: 90%

A High Content Screen in Macrophages Identifies Small Molecule Modulators of STING-IRF3 and NFkB Signaling

Koch

Miller²,

Yu³

et al. 2018

ACS Chem. Biol.

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Summary We screened a library of bioactive small molecules for activators and inhibitors of innate immune signaling through IRF3 and NFkB pathways with the goals of advancing pathway understanding and discovering probes for immunology research. We used high content screening to measure the translocation from the cytoplasm to nucleus of IRF3 and NFkB in primary human macrophages; these transcription factors play a critical role in the activation of STING and other pro-inflammatory pathways. Our pathway activator screen yielded a diverse set of hits that promoted nuclear translocation of IRF3 and/or NFkB, but the majority of these compounds did not cause activation of downstream pathways. Screening for antagonists of the STING pathway yielded multiple kinase inhibitors, some of which inhibit kinases not previously known to regulate the activity of this pathway. Structure-activity relationships (SAR) and subsequent chemical proteomics experiments suggested that MAPKAPK5 (PRAK) is a kinase that regulates IRF3 translocation in human macrophages. Our work establishes a high content screening approach for measuring pro-inflammatory pathways in human macrophages and identifies novel ways to inhibit such pathways; among the targets of the screen are several molecules that may merit further development as anti-inflammatory drugs.

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Section: Resultssupporting

confidence: 90%

A High Content Screen in Macrophages Identifies Small Molecule Modulators of STING-IRF3 and NFkB Signaling

Koch

Miller²,

Yu³

et al. 2018

ACS Chem. Biol.

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“…Further, within the STING Western blot and the IFNβ mRNA data, there is an interesting and hypothesis‐generating tissue‐specific finding. It is known that intracellular trafficking and proteasomal degradation regulate activated STING levels . We noted that mice ‘l’, ‘m’ and ‘n’ exhibited differential levels of STING in splenocytes versus lung cells in the Western blot, and versus control mice ‘j’ and ‘k’ in lung cells.…”

Section: Discussionmentioning

confidence: 90%

cAIMP administration in humanized mice induces a chimerization‐level‐dependent STING response

et al. 2019

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Summary It is well understood that the STING signalling pathway is critical for generating a robust innate immune response to pathogens. Human and mouse STING signalling pathways are not identical, however. For example, mice lack IFI16, which has been proven important for the human STING pathway. Therefore, we investigated whether humanized mice are an appropriate experimental platform for exploring the human STING signalling cascade in vivo. We found that NOG mice reconstituted with human cord blood haematopoietic stem cells (humanized NOG mice) exhibit human STING signalling responses to an analogue of the cyclic di‐nucleotide cGAMP. There was an increase in the proportions of monocytes in the lungs of mice receiving cGAMP analogue. The most robust levels of STING expression and STING‐induced responses were observed in mice exhibiting the highest levels of human chimerization. Notably, differential levels of STING in lung versus spleen following cGAMP analogue treatment suggest that there are tissue‐specific kinetics of STING activation and/or degradation in effector versus inductive sites. We also examined the mouse innate immune response to cGAMP analogue treatment. We detected that mouse cells in the immunodeficient NOG mice responded to the cGAMP analogue and they do so with distinct kinetics from the human response. In conclusion, humanized NOG mice represent a valuable experimental model for examining in vivo human STING responses.

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“…Immunofluorescent microscopy has shown that, at later time points, STING co‐localizes with Rab7‐containing vesicles (late endosome/lysosome) but not vesicles containing Rab5 (early endosome) or Rab11 (recycling endosomes). Inhibiting lysosomal function by blocking acidification prevents activation‐induced STING degradation . To prevent chronic cGAS activation, the STING pathway also induces autophagy and this is thought to help clear cytosolic DNA.…”

Section: Basic Biology Of the Sting Pathwaymentioning

confidence: 99%

“…Thus, cytosolic DNA initiates a cGAS‐STING‐TBK1‐IRF3 signaling cascade that induces a type I IFN response, and signaling becomes resolved by degradation of components of the STING pathway as well as clearance of the stimulatory DNA . There are many post‐translational modifications of both cGAS and STING that regulate their function and allow cross‐talk of the STING pathway with other cellular processes.…”

Section: Basic Biology Of the Sting Pathwaymentioning

confidence: 99%

“…Blocking endolysosome acidification with bafilomycin A1 (BaFA1) can also support STING signaling by preventing STING degradation. Intratumoral injection of cGAMP and BaFA1 in B16 subcutaneous tumors resulted in improved tumor control compared to cGAMP alone . As our molecular understanding of the STING pathway and its regulation improves, there will likely be additional opportunities for STING pathway therapeutic targeting beyond administration of cyclic dinucleotides.…”

Section: Sting Pathway Involvement In Anti‐tumor Immunity In Preclinimentioning

confidence: 99%

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STING pathway agonism as a cancer therapeutic

Flood

Higgs

et al. 2019

Immunological Reviews

229

183

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The fact that a subset of human cancers showed evidence for a spontaneous adaptive immune response as reflected by the T cell‐inflamed tumor microenvironment phenotype led to the search for candidate innate immune pathways that might be driving such endogenous responses. Preclinical studies indicated a major role for the host STING pathway, a cytosolic DNA sensing pathway, as a proximal event required for optimal type I interferon production, dendritic cell activation, and priming of CD8+ T cells against tumor‐associated antigens. STING agonists are therefore being developed as a novel cancer therapeutic, and a greater understanding of STING pathway regulation is leading to a broadened list of candidate immune regulatory targets. Early phase clinical trials of intratumoral STING agonists are already showing promise, alone and in combination with checkpoint blockade. Further advancement will derive from a deeper understanding of STING pathway biology as well as mechanisms of response vs resistance in individual cancer patients.

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

Cited by 219 publications

References 22 publications

A High Content Screen in Macrophages Identifies Small Molecule Modulators of STING-IRF3 and NFkB Signaling

A High Content Screen in Macrophages Identifies Small Molecule Modulators of STING-IRF3 and NFkB Signaling

cAIMP administration in humanized mice induces a chimerization‐level‐dependent STING response

STING pathway agonism as a cancer therapeutic

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