The Ras GTPase-activating-like protein IQGAP1 bridges Gasdermin D to the ESCRT system to promote IL-1β release via exosomes.
The Ras GTPase-activating-like protein IQGAP1 bridges Gasdermin D to the ESCRT system to promote IL-1β release via exosomes.
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DOI：
10.15252/embj.2022110780
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发表时间：
2023-01-04
期刊：
影响因子：
11.4
通讯作者：
Li, Xiaoxia
中科院分区：
文献类型：
--
作者：
Liao, Yun;Chen, Xing;Miller-Little, William;Wang, Han;Willard, Belinda;Bulek, Katarzyna;Zhao, Junjie;Li, Xiaoxia
IL-1β可以以Gasdermin D（GSDMD）依赖性方式在肠上皮细胞（IEC）中的炎性小体激活后作为外泌体货物离开胞质溶胶。迄今为止，连接炎性体激活和外来体生物发生的机制联系在很大程度上仍然是难以捉摸的。在这里，我们报告了Ras GT3激活样蛋白IQGAP 1作为衔接子的功能，将GSDMD桥接至转运所需的内体分选复合物（ESCRT）机制，以促进含IL-1β前体的外泌体响应NLPR 3炎性体激活的生物发生。我们通过无偏倚蛋白质组学分析将IQGAP 1鉴定为GSDMD相互作用蛋白。功能研究表明，IQGAP 1-GSDMD相互作用是LPS和ATP诱导的外泌体释放所必需的。进一步的分析表明，IQGAP 1作为衔接子，将GSDMD和相关的IL-1β复合物连接到Tsg 101（ESCRT复合物的一种组分），并使GSDMD和IL-1β包装到外泌体中。重要的是，这一过程依赖于LPS诱导的GTP结合的CDC 42的增加，这是一种已知激活IQGAP 1的小GTP酶。总之，这项研究揭示了IQGAP 1作为炎性小体活化与GSDMD依赖性、ESCRT介导的IL-1β外泌体释放之间的联系。衔接蛋白IQGAP 1通过与Gasdermin D的相互作用将炎性小体激活与货物选择和外泌体释放联系起来。
IL‐1β can exit the cytosol as an exosomal cargo following inflammasome activation in intestinal epithelial cells (IECs) in a Gasdermin D (GSDMD)‐dependent manner. The mechanistic connection linking inflammasome activation and the biogenesis of exosomes has so far remained largely elusive. Here, we report the Ras GTPase‐activating‐like protein IQGAP1 functions as an adaptor, bridging GSDMD to the endosomal sorting complexes required for transport (ESCRT) machinery to promote the biogenesis of pro‐IL‐1β‐containing exosomes in response to NLPR3 inflammasome activation. We identified IQGAP1 as a GSDMD‐interacting protein through a non‐biased proteomic analysis. Functional investigation indicated the IQGAP1‐GSDMD interaction is required for LPS and ATP‐induced exosome release. Further analysis revealed that IQGAP1 serves as an adaptor which bridges GSDMD and associated IL‐1β complex to Tsg101, a component of the ESCRT complex, and enables the packaging of GSDMD and IL‐1β into exosomes. Importantly, this process is dependent on an LPS‐induced increase in GTP‐bound CDC42, a small GTPase known to activate IQGAP1. Taken together, this study reveals IQGAP1 as a link between inflammasome activation and GSDMD‐dependent, ESCRT‐mediated exosomal release of IL‐1β. The adaptor protein IQGAP1 links inflammasome activation to cargo selection and exosome release via the interaction with Gasdermin D.
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影响因子：
21.3
作者：
Claude-Taupin A;Jia J;Bhujabal Z;Garfa-Traoré M;Kumar S;da Silva GPD;Javed R;Gu Y;Allers L;Peters R;Wang F;da Costa LJ;Pallikkuth S;Lidke KA;Mauthe M;Verlhac P;Uchiyama Y;Salemi M;Phinney B;Tooze SA;Mari MC;Johansen T;Reggiori F;Deretic V
通讯作者：
Deretic V
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
DOI：
10.1074/jbc.m112.435941
发表时间：
2013-03-22
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Hong L;Kenney SR;Phillips GK;Simpson D;Schroeder CE;Nöth J;Romero E;Swanson S;Waller A;Strouse JJ;Carter M;Chigaev A;Ursu O;Oprea T;Hjelle B;Golden JE;Aubé J;Hudson LG;Buranda T;Sklar LA;Wandinger-Ness A
通讯作者：
Wandinger-Ness A
影响因子：
7.3
作者：
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通讯作者：
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影响因子：
32.4
作者：
Duong, Bao H.;Onizawa, Michio;Oses-Prieto, Juan A.;Advincula, Rommel;Burlingame, Alma;Malynn, Barbara A.;Ma, Averil
通讯作者：
Ma, Averil