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USP3 deubiquitinates and stabilizes the adapter protein ASC to regulate inflammasome activation

Cellular & Molecular Immunology 2022年第10期19卷 1141-1152页

作者： Wanxin Zhuang Lei Zhang Yi Zheng Bingyu Liu Chunhong Ma Wei Zhao Suxia Liu Feng Liu Chengjiang Gao key Laboratory of Infection and Immunity of Shandong Province&key Laboratory for Experimental Teratology of Ministry of Education Shandong UniversityJinanShandong250012PR China Department of Immunology School of Biomedical SciencesShandong UniversityJinanShandong250012PR China

Inflammasomes are essential components of the innate immune system and its defense against infections,whereas the dysregulation of inflammasome activation has a detrimental effect on human health.The activation of inflammasomes is subjected to tight regulation to maintain immune homeostasis,yet the underlying mechanism remains elusive.Here,we identify USP3 as a direct deubiquitinating enzyme(DUB)for ASC,the central adapter mediating the assembly and activation of most inflammasomes.USP3 removes the k48-linked ubiquitination on ASC and strengthens its stability by blocking proteasomal degradation.Additionally,USP3 promotes inflammasome activation,and this function was confirmed in mouse models of aluminum(Alum)-induced peritonitis,F.novicida infection and flagellin-induced pneumonia in vivo.Our work unveils that USP3 functions as a key regulator of ASC ubiquitination and maintains the physiological role of ASC in mediating inflammasome activation,and we propose a new mechanism by which the ubiquitination of ASC regulates inflammasome activation.

关键词： ASC inflammasome k48-linked ubiquitination proteasomal degradation USP3

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Activation of insulin-like growth factor-1 receptor (IGF-1R) promotes growth of colorectal cancer through triggering the MEX3A-mediated degradation of RIG-Ⅰ

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药学学报:英文版 2023年第7期13卷 2963-2975页

作者： Qiaobo Xie Yanyan Chu Wenmin Yuan Yanan Li keqin Li Xinfeng Wu Xiaohui Liu Rui Xu Shuxiang Cui Xianjun Qu Department of Pharmacology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China Ocean University of China School of Medicine and PharmacyQingdao 266075China Marine Biomedical Research Institute of Qingdao Qingdao 266075China Department of Toxicology and Sanitary Chemistry Beijing Key Laboratory of Environmental ToxicologySchool of Public HealthCapital Medical UniversityBeijing 100069China

Insulin-like growth factor-1 receptor(IGF-1R) has been made an attractive anticancer target due to its overexpression in cancers.However,targeting it has often produced the disappointing results as the role played by cross talk with numerous downstream signalings.Here,we report a disobliging IGF-1R signaling which promotes growth of cancer through triggering the E3 ubiquitin ligase MEX3A-mediated degradation of RIG-I.The active β-arrestin-2 scaffolds this disobliging signaling to talk with MEX3A.In response to ligands,IGF-1Rβ activated the basal βarr2 into its active state by phosphorylating the interdomain domain on Tyr64 and Tyr250,opening the middle loop(Leu130-Cys141) to the RING domain of MEX3A through the conformational changes of βarr2.The models of βarr2/IGF-1Rβ and βarr2/MEX3A could interpret the mechanism of the activated-IGF-1R in triggering degradation of RIG-I.The assay of the mutants βarr2Y64Aand βarr2Y250Afurther confirmed the role of these two Tyr residues of the interlobe in mediating the talk between IGF-1Rβ and the RING domain of MEX3A.The truncated-βarr2 and the peptide ATQAIRIF,which mimicked the RING domain of MEX3A could prevent the formation of βarr2/IGF-1Rβ and βarr2/MEX3A complexes,thus blocking the IGF-1R-triggered RIG-I degradation.Degradation of RIG-I resulted in the suppression of the IFN-I-associated immune cells in the TME due to the blockade of the RIG-I-MAVS-IFN-I pathway.Poly(I:C) could reverse anti-PD-L1 insensitivity by recovery of RIG-I.In summary,we revealed a disobliging IGF-1R signaling by which IGF-1Rβ promoted cancer growth through triggering the MEX3A-mediated degradation of RIG-I.

关键词： IGF-1R RIG-Iβ-Arrestin-2(βarr2) k48-linked ubiquitination MEX3A Anti-PD-L1

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