Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response.
Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response.
复制标题
DOI：
10.1016/j.celrep.2017.11.061
复制
发表时间：
2017-12-12
期刊：
影响因子：
8.8
通讯作者：
Yan N
中科院分区：
文献类型：
--
作者：
Gonugunta VK;Sakai T;Pokatayev V;Yang K;Wu J;Dobbs N;Yan N
STING是一种ER相关的跨膜蛋白，当它从ER易位到囊泡时，它打开并快速关闭下游信号传导。STING信号在贩运过程中如何衰减仍然知之甚少。在这里，我们表明，交通介导的STING降解需要ER-退出，液泡ATP酶复合物的功能，和后期STING囊泡被分选到Rab 7阳性内溶酶体降解。基于对现有结构的分析，我们还鉴定了螺旋aa 281 -297作为贩运介导的STING降解所需的基序。免疫-EM揭示了STING囊泡的大小和聚集以及囊泡上STING的拓扑结构。重要的是，使用巴弗洛霉素A1阻断运输介导的STING降解特异性增强了小鼠中cGAMP介导的免疫应答和抗肿瘤作用。总之，我们的研究结果为溶酶体降解STING提供了生物化学和成像证据，并将贩运介导的STING降解作为先前未预料到的治疗靶点，用于增强癌症治疗中的STING信号传导。STING激活打开并快速关闭下游信号传导，因为它通过分泌途径运输。Gonugunta等人发现，运输介导的STING降解需要ER退出并将STING囊泡分选至溶酶体以进行降解。阻断STING降解增强STING信号传导和抗肿瘤反应。
STING is an ER-associated transmembrane protein that turns on and quickly turns off downstream signaling as it translocates from the ER to vesicles. How STING signaling is attenuated during trafficking remains poorly understood. Here, we show that trafficking-mediated STING degradation requires ER-exit, function of vacuolar ATPase complex, and late stage STING vesicles are sorted to Rab7-positive endolysosomes for degradation. Based on analysis of existing structures, we also identified the helix aa281-297 as a motif required for trafficking-mediated STING degradation. Immuno-EM reveals the size and clustering of STING vesicles and topology of STING on the vesicle. Importantly, blockade of trafficking-mediated STING degradation using bafilomycin A1 specifically enhanced cGAMP-mediated immune response and anti-tumor effect in mice. Together, our findings provide biochemical and imaging evidence for STING degradation by the lysosome, and pinpoint trafficking-mediated STING degradation as a previously unanticipated therapeutic target for enhancing STING signaling in cancer therapy. STING activation turns on and quickly turns off downstream signaling as it is trafficked through the secretory pathway. Gonugunta et al. found that trafficking-mediated STING degradation requires ER exit and sorting of STING vesicles to lysosomes for degradation. Blockade of STING degradation enhances STING signaling and anti-tumor response.
登录
查看更多内容
影响因子：
13.3
作者：
Finn, Patrick E.;Mesires, Nicholas T.;Dice, J. Fred
通讯作者：
Dice, J. Fred
影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1126/science.1244040
发表时间：
2013-09-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li XD;Wu J;Gao D;Wang H;Sun L;Chen ZJ
通讯作者：
Chen ZJ
S6K刺激相互作用调节胞质DNA介导的转录因子IRF3的激活。
影响因子：
30.5
作者：
Wang F;Alain T;Szretter KJ;Stephenson K;Pol JG;Atherton MJ;Hoang HD;Fonseca BD;Zakaria C;Chen L;Rangwala Z;Hesch A;Chan ESY;Tuinman C;Suthar MS;Jiang Z;Ashkar AA;Thomas G;Kozma SC;Gale M Jr;Fitzgerald KA;Diamond MS;Mossman K;Sonenberg N;Wan Y;Lichty BD
通讯作者：
Lichty BD
影响因子：
64.5
作者：
Konno H;Konno K;Barber GN
通讯作者：
Barber GN