HER2 Blocks the cGAS–STING-Mediated Immune Response to DNA Damage

The presence of DNA fragments in the cytosol normally triggers activation of the cGAS–STING pathway, eliciting a response from the innate immune system. However, DNA fragments are abundant in the cytosols of many cancer cell types, and it is not clear how they evade this form of immune surveillance. Wu, Zhang, Zhang, and colleagues discovered that cGAS–STING signaling is inhibited by the receptor tyrosine kinase and key oncoprotein HER2 (also known as ERBB2) in a dose-dependent manner. This effect was specific to HER2; other members of the HER family did not impair cGAS–STING signaling. Further, small-molecule HER2 inhibitors enhanced cytosolic DNA sensing in human cells and potentiated STING-dependent TBK1 activation, and HER2 knockout increased cytosolic DNA sensing. Additionally, expression of HER2′s intracellular domain disrupted formation of the STING signalosome. HER2 appeared to recruit AKT1 (also known as PKB) to STING, upon which AKT1 altered the phosphorylation profile of the STING signalosome's central kinase, TBK1; notably, phosphorylation at S510 was dramatically increased. STING–TBK1 and IRF3–TBK1 interactions were substantially reduced in this context, attenuating STING signaling. Providing further evidence for HER2′s role in blocking cytosolic DNA sensing and broadening the relevance of these findings, HER2 also dampened the innate immune response to viral DNA in the cytosol and blocked damage-induced senescence and apoptosis. In a mouse xenograft model, HER2 shielded cancer cells from STING-mediated antitumor effects. Together, these results reveal a previously unknown function of HER2 and suggest that further studies on how HER2 interacts with the cGAS–STING pathway—and on whether its activity in this pathway affects cancer pathogenesis or drug response—are warranted.

Wu S, Zhang Q, Zhang F, Meng F, Liu S, Zhou R, et al. HER2 recruits AKT1 to disrupt STING signalling and suppress antiviral defence and antitumour immunity. Nat Cell Biol 2019;21:1027–40.

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