Research ArticleHOST DEFENSE

Ubiquitination of STING at lysine 224 controls IRF3 activation

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Science Immunology  05 May 2017:
Vol. 2, Issue 11, eaah7119
DOI: 10.1126/sciimmunol.aah7119

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Fine-tuning the STING

In eukaryotic cells, cytosolic DNA is often an indicator of viral infection. STING (stimulator of interferon genes), an endoplasmic reticulum–associated protein, is a central node that connects cytosolic DNA sensing with transcription factors (such as interferon regulatory factors) that drive antiviral host responses. STING activation is tightly regulated. Chronic STING activation has been documented in autoinflammatory settings, whereas STING agonists are being considered as a means to activate innate immune responses to cancers. Here, Ni et al. show that MUL1 (mitochondrial E3 ubiquitin protein ligase 1) ubiquitinates STING at lysine 224 to promote STING-dependent production of antiviral cytokines and chemokines. By extending our understanding of STING activation, these studies may lead to new approaches to modulating STING activation in various settings.


Cytosolic DNA species derived from invading microbes or leaked from the nuclear or mitochondrial compartments of the cell can trigger the induction of host defense genes by activating the endoplasmic reticulum–associated protein STING (stimulator of interferon genes). Using a mass spectrometry–based approach, we show that after association with cyclic dinucleotides, delivery of Tank-binding kinase 1 to interferon regulatory factors (IRFs), such as IRF3, relies on K63-linked ubiquitination of K224 on STING. Blocking K224 ubiquitination specifically prevented IRF3 but not nuclear factor κB activation, additionally indicating that STING trafficking is not required to stimulate the latter signaling pathway. By carrying out a limited small interfering RNA screen, we have identified MUL1 (mitochondrial E3 ubiquitin protein ligase 1) as an E3 ligase that catalyzes the ubiquitination of STING on K224. These data demonstrate the critical role of K224 ubiquitination in STING function and provide molecular insight into the mechanisms governing host defense responses.

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