STING activation by translocation from the ER is associated with infection and autoinflammatory disease

Nicole Dobbs, Nikolay Burnaevskiy, Didi Chen, Vijay K. Gonugunta, Neal M. Alto, Nan Yan

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

STING is an ER-associated membrane protein that is critical for innate immune sensing of pathogens. STING-mediated activation of the IFN-I pathway through the TBK1/IRF3 signaling axis involves both cyclic-dinucleotide binding and its translocation from the ER to vesicles. However, how these events are coordinated, and the exact mechanism of STING activation, remain poorly understood. Here, we found that the Shigella effector protein IpaJ potently inhibits STING signaling by blocking its translocation from the ER to ERGIC, even in the context of dinucleotide binding. Reconstitution using purified components revealed STING translocation as the rate-limiting event in maximal signal transduction. Furthermore, STING mutations associated with autoimmunity in humans were found to cause constitutive ER exit and to activate STING independent of cGAMP binding. Together, these data provide compelling evidence for an ER retention and ERGIC/Golgi-trafficking mechanism of STING regulation that is subverted by bacterial pathogens and is deregulated in human genetic disease.

Original languageEnglish (US)
Pages (from-to)157-168
Number of pages12
JournalCell Host and Microbe
Volume18
Issue number2
DOIs
StatePublished - Aug 12 2015

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Inborn Genetic Diseases
Shigella
Medical Genetics
Autoimmunity
Signal Transduction
Membrane Proteins
Mutation
Infection
Proteins
cyclic guanosine monophosphate-adenosine monophosphate

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Cancer Research
  • Molecular Biology

Cite this

STING activation by translocation from the ER is associated with infection and autoinflammatory disease. / Dobbs, Nicole; Burnaevskiy, Nikolay; Chen, Didi; Gonugunta, Vijay K.; Alto, Neal M.; Yan, Nan.

In: Cell Host and Microbe, Vol. 18, No. 2, 12.08.2015, p. 157-168.

Research output: Contribution to journalArticle

Dobbs, Nicole ; Burnaevskiy, Nikolay ; Chen, Didi ; Gonugunta, Vijay K. ; Alto, Neal M. ; Yan, Nan. / STING activation by translocation from the ER is associated with infection and autoinflammatory disease. In: Cell Host and Microbe. 2015 ; Vol. 18, No. 2. pp. 157-168.
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