得克萨斯大学西南医学中心Nan Yan团队近日取得一项新成果。经过不懈努力，他们的论文发现了COPII货物识别的STING信号调制。相关论文发表在2026年3月25日出版的《细胞》杂志上。
研究团队发现EEΦxΦ （339EEVTV343 in human STING）是SEC24同源物C（SEC24C）识别的ER退出基序。使用AlphaFold3，课题组提出了SEC24C与STING二聚体结合的预测结构，揭示了先前结构未确定区域的EEΦxΦ基序。该基序或SEC24C货物结合位点的突变会破坏STING的转运和信号传导。他们的研究结果支持STING寡聚化和贪婪阈值模型，该模型解释了调控内质网退出。EEΦxΦ基序在脊椎动物STING同源物中是保守的，足以介导不相关蛋白的内质网退出。
有趣的是，与已知的SEC24C基序相比，STING ER退出基序是次优的，而SEC24C基序对于防止免疫过度激活至关重要。一个工程的“超级ER出口”STING是组成活性和诱导有效的抗肿瘤免疫。串联重复序列竞争性地抑制内源性STING信号。总的来说，本研究阐明了STING-ER退出机制，并提出了调节STING信号的策略。
据了解，干扰素基因刺激因子（STING）激活需要衣壳蛋白复合物II （COPII）介导的内质网（ER）退出，但其机制尚不清楚。
附：英文原文
Title: STING signaling modulation by COPII cargo recognition
Author: Heng Lyu, Cong Xing, Wanwan Huai, Kun Song, Devon Jeltema, Hui Zhang, Xuewu Zhang, Nan Yan
Issue&Volume: 2026-03-25
Abstract: Stimulator of interferon genes (STING) activation requires coat protein complex II (COPII)-mediated endoplasmic reticulum (ER) exit, but the mechanism remains elusive. Here, we identify EEΦxΦ (339EEVTV343 in human STING) as the ER-exit motif recognized by SEC24 homolog C (SEC24C). Using AlphaFold3, we present a predicted structure of SEC24C binding to a STING dimer, revealing the EEΦxΦ motif in a previously structurally unresolved region. Mutations in this motif or the SEC24C cargo-binding site disrupt STING trafficking and signaling. Our findings support a STING oligomerization and avidity threshold model that explains regulated ER exit. The EEΦxΦ motif is conserved in vertebrate STING homologs and is sufficient to mediate ER exit of unrelated proteins. Interestingly, the STING ER-exit motif is suboptimal compared with known SEC24C cargos, which is crucial for preventing immune overactivation. An engineered “super-ER-exit” STING is constitutively active and induces potent antitumor immunity. Tandem repeats of this motif competitively inhibit endogenous STING signaling. Collectively, this study elucidates the STING-ER-exit mechanism and presents strategies for modulating STING signaling.
DOI: 10.1016/j.cell.2026.02.029
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00267-9