Editors' ChoiceImmunology

HER2 reduces the STING

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Science Signaling  06 Aug 2019:
Vol. 12, Issue 593, eaay9834
DOI: 10.1126/scisignal.aay9834

The receptor tyrosine kinase HER2 inhibits STING activation and limits the immune response to DNA virus infection and cancer.

DNA damage or pathogen invasion can promote intracellular DNA recognition by cyclic GMP–AMP synthase (cGAS), which stimulates downstream stimulator of interferon genes (STING)–dependent signaling and immunity. Activation of this cGAS-STING pathway is tightly controlled, and its dysregulation is linked to the development of autoimmune diseases. To identify kinases that may play a role in STING activation, Wu et al. screened a cDNA library of kinases and showed that selective expression of the receptor tyrosine kinase HER2 (also known as ERBB2) inhibited STING-dependent activation of an IRF3-driven luciferase reporter. Both HER2 inhibition and loss of HER2 promoted STING-dependent activation of interferon-stimulated genes in cell lines. HER2 interacted with endogenous STING in colorectal adenocarcinoma cells, and expression of its intracellular domain prevented the interaction of STING with the downstream kinase TBK1, as well as K63 ubiquitylation of the adaptor protein TNF receptor–associated factor 6 (TRAF6), which are hallmarks of STING signalosome assembly. Although, HER2 itself did not promote the phosphorylation of STING signalosome components, this activity correlated with HER2-dependent AKT activation. In vitro kinase assays showed that purified AKT1 stimulated TBK1 phosphorylation, and mass spectrometry analysis identified the specific target site, which corresponded with the known AKT1 substrate motif. CRISPR modification of those residues in TBK1 enhanced both endogenous and STING-mediated activation of TBK1 and IRF3. In vitro and in vivo, HER2 inhibitors limited infection with the DNA virus HSV-1. In contrast, overexpression of HER2 reduced the cellular response to DNA-damaging agents and promoted the growth of melanoma xenografts with constitutive STING activation. These data identify a previously uncharacterized way in which DNA sensing is inhibited (see commentary by Odell and Flavell). Critically, this study suggests that care should be taken when considering combining targeted agents against HER2 or the related receptor EGFR with programmed death ligand 1 immunotherapy, which in some conditions requires STING activity for efficacy.

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