Article
Multidisciplinary Sciences
Debipreeta Bhowmik, Yuan Tian, Bing Wang, Fanxiu Zhu, Qian Yin
Summary: KicGAS is a conserved major tegument protein of KSHV, which forms an oligomerized chain structure and interacts with DNA to restrict cGAS activation and inhibit viral growth.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Dapeng Ma, Min Yang, Qiushi Wang, Caiyu Sun, Hongbiao Shi, Weiqiang Jing, Yuxuan Bi, Xuecheng Shen, Xiaomin Ma, Zhenzhi Qin, Yueke Lin, Lihui Zhu, Yunxue Zhao, Yeping Cheng, Lihui Han
Summary: PRMT5 catalyzes arginine symmetrical dimethylation of cGAS, attenuating the antiviral immune response by blocking cGAS' DNA binding ability. Inhibitors of PRMT5 protect mice from HSV-1 infection and prolong their survival time, indicating the potential of modulating PRMT5 as an antiviral strategy.
Article
Virology
Qianqian Xie, Jigui Wang, Jun Su, Chenchen Gu, Jing Wu, Jun Xiao, Weiquan Liu
Summary: The NS1 protein of mink enteritis virus (MEV) is a multifunctional protein with nuclease, helicase, and transactivation activities. Mutations in potential amino acids critical for DNA binding in the MEV NS1 resulted in a termination of viral production. Different mutations affected the transactivation activity and integrity of the NS1 protein as well as its ability to interact with SP1 and bind to the DNA-binding sites in the P38 promoter, leading to transcriptional repression.
Article
Chemistry, Multidisciplinary
Lina Wang, Qiaoling Liu, Na Wang, Siru Li, Wei Bian, Zhen Sun, Lulu Wang, Li Wang, Caigang Liu, Chengli Song, Quentin Liu, Qingkai Yang
Summary: Phase separation is a fundamental principle in various life processes, including immunosurveillance. This study reveals that oleic acid can dissolve the phase separation of cGAS-DNA and inhibit immune surveillance of DNA. Long-chain fatty acids, including oleic acid, can dissolve the cGAS-DNA condensates formed via phase separation. Oleic acid attenuates cGAS-mediated antiviral and anticancer immunosurveillance by dissolving phase separation. These findings highlight the link between metabolism and immunity and suggest potential therapeutic interventions.
Editorial Material
Cell Biology
Paula Juricic, Andrea Ablasser
Summary: TREX1 antagonizes DNA-mediated cGAS activation, playing a crucial role in preventing autoimmunity. New aspects of this important control mechanism are uncovered in studies by Mohr et al. (2021) and Zhou et al. (2021).
DEVELOPMENTAL CELL
(2021)
Article
Immunology
Nina Kessler, Susanne F. Viehmann, Calvin Krollmann, Karola Mai, Katharina M. Kirschner, Hella Luksch, Prasanti Kotagiri, Alexander M. C. Boehner, Dennis Huugen, Carina C. de Oliveira Mann, Simon Otten, Stefanie A. Weiss, Thomas Zillinger, Kristiyana Dobrikova, Dieter E. Jenne, Rayk Behrendt, Andrea Ablasser, Eva Bartok, Gunther Hartmann, Karl-Peter Hopfner, Paul A. Lyons, Peter Boor, Angela Roesen-Wolff, Lino L. Teichmann, Peter Heeringa, Christian Kurts, Natalio Garbi
Summary: The study identifies abnormal DNA recognition and IFN-I production as drivers of severe ANCA-associated vasculitis, and demonstrates that blocking this pathway can ameliorate the disease and accelerate recovery, suggesting potential therapeutic targets for patients.
JOURNAL OF EXPERIMENTAL MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Yizeng Fan, Yang Gao, Li Nie, Tao Hou, Weichao Dan, Zixi Wang, Tianjie Liu, Yi Wei, Yuzhao Wang, Bo Liu, Taotao Que, Yuzeshi Lei, Jin Zeng, Jian Ma, Wenyi Wei, Lei Li
Summary: Research has shown that LYPLAL1-mediated depalmitoylation of cGAS can enhance its activity, thus improving the efficacy of anti-tumor immune responses.
Article
Biochemical Research Methods
Robert W. Gregg, Fathima Shabnam, Jason E. Shoemaker
Summary: The study revealed that cell heterogeneity can enhance IFN beta responses during infection. Only 20-30% of cells need to respond during infection, beyond which no additional protection against cell death or reduction of viral load is provided.
Article
Multidisciplinary Sciences
Yu-Hsuan Chen, Han-Hsiun Chen, Won-Jing Wang, Hsin-Yi Chen, Wei-Syun Huang, Chien-Han Kao, Sin-Rong Lee, Nai Yang Yeat, Ruei-Liang Yan, Shu-Jou Chan, Kuen-Phon Wu, Ruey-Hwa Chen
Summary: Activation of tumor-intrinsic innate immunity is crucial for improving immunotherapy. The deubiquitinating enzyme TRABID is found to play a suppressive role in anti-tumor immunity by regulating mitotic cell division and activating the cGAS/STING pathway. TRABID inhibition induces micronuclei and protects cGAS from autophagy, thus promoting anti-tumor immune responses.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Wen Zhou, Lisa Mohr, John Maciejowski, Philip J. Kranzusch
Summary: The phase separation of cGAS-DNA is critical for efficient sensing of immunostimulatory DNA, as it limits the activity of the cytosolic exonuclease TREX1. This selective environment suppresses TREX1 function and restricts DNA degradation, balancing cytosolic DNA degradation and innate immune activation.
Article
Oncology
Shunsuke Kitajima, Tetsuo Tani, Benjamin F. Springer, Marco Campisi, Tatsuya Osaki, Koji Haratani, Minyue Chen, Erik H. Knelson, Navin R. Mahadevan, Jessica Ritter, Ryohei Yoshida, Jens Kohler, Atsuko Ogino, Ryu-Suke Nozawa, Shriram K. Sundararaman, Tran C. Thai, Mizuki Homme, Brandon Piel, Sophie Kivlehan, Bonje N. Obua, Connor Purcell, Mamiko Yajima, Thanh U. Barbie, Patrick H. Lizotte, Pasi A. Janne, Cloud P. Paweletz, Prafulla C. Gokhale, David A. Barbie
Summary: KRAS-LKB1 mutant lung cancers silence the STING pathway and minimize intracellular accumulation of 2'3'-cGAMP to avoid T cell infiltration and decrease response to PD-1 blockade. However, transient MPS1 inhibition can re-activate the STING pathway in KL cells and restore T cell infiltration, enhancing the efficacy of anti-PD-1 treatment.
Article
Medicine, Research & Experimental
Grace Oh, Annie Wang, Lidong Wang, Jiufeng Li, Gregor Werba, Daniel Weissinger, Ende Zhao, Surajit Dhara, Rosmel E. Hernandez, Amanda Ackermann, Sarina Porcella, Despoina Kalfakakou, Igor Dolgalev, Emily Kawaler, Talia Golan, Theodore H. Welling, Agnel Sfeir, Diane M. Simeone
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with specific vulnerabilities to certain therapies. Inactivation of the HR pathway and overexpression of POLQ are associated with PDAC. Knockdown of POLQ enhances tumor immune infiltration and can be used as a synthetic lethal approach to inhibit tumor growth.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Multidisciplinary Sciences
Haiyan Gu, Jing Yang, Jiayu Zhang, Ying Song, Yao Zhang, Pengfei Xu, Yuanxiang Zhu, Liangliang Wang, Pengfei Zhang, Lin Li, Dahua Chen, Qinmiao Sun
Summary: cGAS is regulated by its interacting protein PCBP2, which controls its enzyme activity and affects cGAS-STING signaling pathway in antiviral response. Overexpression of PCBP2 reduces the antiviral signaling while loss of PCBP2 increases cGAS activity. PCBP2 decreases cGAS enzyme activity by antagonizing cGAS condensation, ensuring appropriate cGAMP production and balanced cGAS-STING signal transduction.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Physical
Jingjing Guo, Mengrong Li, Yan Zhang, Lili Xi, Fengling Cui
Summary: This study used molecular dynamics simulations to uncover allosteric inhibition mechanisms of cGAS by mimicking acetylation. The results showed that conformational dynamics play a vital role in this process, with mutations affecting cGAS activity.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2021)
Article
Multidisciplinary Sciences
Lina Wang, Siru Li, Kai Wang, Na Wang, Qiaoling Liu, Zhen Sun, Li Wang, Lulu Wang, Quentin Liu, Chengli Song, Caigang Liu, Qingkai Yang
Summary: The activation of cyclic GMP-AMP synthase (cGAS) is influenced by the mechanical flexibility of DNA, which is determined by DNA-sequence, damage, and length. Low dose radiation can induce cGAS-mediated acute immune surveillance (AIS) through repairable DNAs in a short period of time. This study establishes a direct connection between immunosurveillance and DNA mechanical features.
NATURE COMMUNICATIONS
(2022)
Editorial Material
Immunology
Jianjun Wu, Nan Yan
Summary: A recent study identified an innate-like cytosolic DNA-sensing mechanism in aged CD4(+) T cells, driven by the KU complex, which exacerbates aging-related autoimmunity.
Article
Multidisciplinary Sciences
Ting-Ting Chu, Xintao Tu, Kun Yang, Jianjun Wu, Joyce J. Repa, Nan Yan
Summary: This study identifies a cGAS- and cGAMP-independent mode of STING activation that affects neuropathology and provides a therapeutic target for the treatment of Niemann-Pick disease type C.
Article
Multidisciplinary Sciences
Shuiqing Hu, Yan Fang, Xiang Chen, Tianlei Cheng, Miaoqing Zhao, Mingjian Du, Tuo Li, Minghao Li, Zhiqun Zeng, Yonglong Wei, Zhimin Gu, Conggang Zhang, Lijun Sun, Zhijian J. Chen
Summary: cGAS plays a crucial role in controlling the development of colitis-associated colon cancer by defending the integrity of the intestinal mucosa, suppressing inflammation, and promoting the proliferation of intestinal epithelial cells.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Biochemistry & Molecular Biology
Jianjun Wu, Nan Yan
Summary: This review article summarizes the important role of stimulator of interferon genes (STING) in infection, autoimmune disease, and cancer. It focuses on the evolutionary origin and molecular mechanisms of STING-mediated interferon-independent activities. The article highlights that STING not only produces interferons, but also functions as a hub that converts multiple environmental cues into diverse cellular responses. These findings provide new insights for the clinical testing of STING agonists in cancer and the treatment of STING-associated human diseases.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Immunology
Xing Yang, Jingfan Zhou, Chengrong Liu, Yafei Qu, Weili Wang, Maggie Z. X. Xiao, Fanxiu Zhu, Zhenshan Liu, Qiming Liang
Summary: The ORF45 protein from Kaposi's sarcoma-associated herpesvirus activates NLRP1 by binding to its Linker1 region using a mechanism distinct from the previously described DPP9-dependent mechanism of NLRP1 activation.
Article
Multidisciplinary Sciences
Debipreeta Bhowmik, Yuan Tian, Bing Wang, Fanxiu Zhu, Qian Yin
Summary: KicGAS is a conserved major tegument protein of KSHV, which forms an oligomerized chain structure and interacts with DNA to restrict cGAS activation and inhibit viral growth.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Yuan Tian, Ishara Datta, Rui Yang, Chun Wan, Bing Wang, Lauren Crisman, Huan He, Chad A. Brautigam, Suzhao Li, Jingshi Shen, Qian Yin
Summary: We found that AAGAB exists as a dimer before binding to AP1/2, and its dimerization is mediated by the C-terminal domain. AAGAB uses the same C-terminal domain to recognize and stabilize the subunits in the AP1 and AP2 complexes, forming binary complexes with only one copy of AAGAB.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Madhurima Bhattacharya, Debipreeta Bhowmik, Yuan Tian, Huan He, Fanxiu Zhu, Qian Yin
Summary: The dengue virus (DENV) can suppress the cGAS-STING signaling pathway by cleaving cGAS into two major cleavage products, CP-N and CP-C. CP-N competitively inhibits the production of cyclic GMP-AMP by full-length cGAS and CP-C, while CP-C reduces its enzyme activity due to decreased DNA-binding affinity. Additionally, the NS2B3 protein physically interacts with full-length cGAS and CP-C, leading to their degradation in the autophagosome. This study provides a multifaceted and effective strategy for designing antivirals targeting viral proteases.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Shifeng Wang, Xu Chen, Lauren Crisman, Ximing Dou, Christina S. Winborn, Chun Wan, Harrison Puscher, Qian Yin, Matthew J. Kennedy, Jingshi Shen
Summary: Surface protein levels are regulated by a Reps1-Ralbp1-RalA module in the exocytic pathway. Reps1 and Ralbp1 form a complex that recognizes RalA and promotes exocytosis. Ralbp1 maintains RalA in an active GTP-bound state, stabilizing its GTP state.
Article
Biochemistry & Molecular Biology
Daria Beshnova, Yan Fang, Mingjian Du, Yehui Sun, Fenghe Du, Jianfeng Ye, Zhijian James Chen, Bo Li
Summary: Coronavirus disease 2019 (COVID-19) caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a severe pandemic worldwide, causing enormous global health and economic damage. Developing effective COVID-19 treatments is an urgent necessity, and the use of computational methods may provide an attractive solution in selecting the top candidates.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2022)