Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
EMBO J. 2020 Nov 16;39(22):e104106. doi: 10.15252/embj.2019104106. Epub 2020 Sep 14.
STING (STimulator of INterferon Genes) mediates protective cellular response to microbial infection and tissue damage, but its aberrant activation can lead to autoinflammatory diseases. Upon ligand stimulation, the endoplasmic reticulum (ER) protein STING translocates to endosomes for induction of interferon production, while an alternate trafficking route delivers it directly to the autophagosomes. Here, we report that phosphorylation of a specific tyrosine residue in STING by the epidermal growth factor receptor (EGFR) is required for directing STING to endosomes, where it interacts with its downstream effector IRF3. In the absence of EGFR-mediated phosphorylation, STING rapidly transits into autophagosomes, and IRF3 activation, interferon production, and antiviral activity are compromised in cell cultures and mice, while autophagic activity is enhanced. Our observations illuminate a new connection between the tyrosine kinase activity of EGFR and innate immune functions of STING and suggest new experimental and therapeutic approaches for selective regulation of STING functions.
STING（干扰素基因刺激物）介导对微生物感染和组织损伤的保护性细胞反应，但它的异常激活可导致自身炎症性疾病。在内质网（ER）蛋白 STING 受到配体刺激后，会转移到内涵体中诱导干扰素产生，而另一种运输途径则将其直接输送到自噬体中。在这里，我们报告 EGFR（表皮生长因子受体）对 STING 特定酪氨酸残基的磷酸化对于将 STING 定向到内涵体是必需的，在内涵体中它与下游效应物 IRF3 相互作用。在没有 EGFR 介导的磷酸化的情况下，STING 会迅速转位到自噬体中，细胞培养物和小鼠中的 IRF3 激活、干扰素产生和抗病毒活性受损，而自噬活性增强。我们的观察结果阐明了 EGFR 的酪氨酸激酶活性与 STING 的先天免疫功能之间的新联系，并为选择性调节 STING 功能提出了新的实验和治疗方法。
