AIM2 Inflammasome Is Activated by Pharmacological Disruption Of
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The Emerging Relevance of AIM2 in Liver Disease
International Journal of Molecular Sciences Review The Emerging Relevance of AIM2 in Liver Disease Beatriz Lozano-Ruiz 1,2 and José M. González-Navajas 1,2,3,4,* 1 Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain; [email protected] 2 Department of Pharmacology, Paediatrics and Organic Chemistry, University Miguel Hernández (UMH), 03550 San Juan, Alicante, Spain 3 Networked Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III, 28029 Madrid, Spain 4 Institute of Research, Development and Innovation in Healthcare Biotechnology in Elche (IDiBE), University Miguel Hernández, 03202 Elche, Alicante, Spain * Correspondence: [email protected]; Tel.: +34-(965)-913-928 Received: 16 August 2020; Accepted: 4 September 2020; Published: 7 September 2020 Abstract: Absent in melanoma 2 (AIM2) is a cytosolic receptor that recognizes double-stranded DNA (dsDNA) and triggers the activation of the inflammasome cascade. Activation of the inflammasome results in the maturation of inflammatory cytokines, such as interleukin (IL)-1 β and IL-18, and a form of cell death known as pyroptosis. Owing to the conserved nature of its ligand, AIM2 is important during immune recognition of multiple pathogens. Additionally, AIM2 is also capable of recognizing host DNA during cellular damage or stress, thereby contributing to sterile inflammatory diseases. Inflammation, either in response to pathogens or due to sterile cellular damage, is at the center of the most prevalent and life-threatening liver diseases. Therefore, during the last 15 years, the study of inflammasome activation in the liver has emerged as a new research area in hepatology. Here, we discuss the known functions of AIM2 in the pathogenesis of different hepatic diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), hepatitis B, liver fibrosis, and hepatocellular carcinoma (HCC). -
Interleukin-18 in Health and Disease
International Journal of Molecular Sciences Review Interleukin-18 in Health and Disease Koubun Yasuda 1 , Kenji Nakanishi 1,* and Hiroko Tsutsui 2 1 Department of Immunology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan; [email protected] 2 Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-798-45-6573 Received: 21 December 2018; Accepted: 29 January 2019; Published: 2 February 2019 Abstract: Interleukin (IL)-18 was originally discovered as a factor that enhanced IFN-γ production from anti-CD3-stimulated Th1 cells, especially in the presence of IL-12. Upon stimulation with Ag plus IL-12, naïve T cells develop into IL-18 receptor (IL-18R) expressing Th1 cells, which increase IFN-γ production in response to IL-18 stimulation. Therefore, IL-12 is a commitment factor that induces the development of Th1 cells. In contrast, IL-18 is a proinflammatory cytokine that facilitates type 1 responses. However, IL-18 without IL-12 but with IL-2, stimulates NK cells, CD4+ NKT cells, and established Th1 cells, to produce IL-3, IL-9, and IL-13. Furthermore, together with IL-3, IL-18 stimulates mast cells and basophils to produce IL-4, IL-13, and chemical mediators such as histamine. Therefore, IL-18 is a cytokine that stimulates various cell types and has pleiotropic functions. IL-18 is a member of the IL-1 family of cytokines. IL-18 demonstrates a unique function by binding to a specific receptor expressed on various types of cells. -
Complementary Regulation of Caspase-1 and IL-1Β Reveals Additional Mechanisms of Dampened Inflammation in Bats
Complementary regulation of caspase-1 and IL-1β reveals additional mechanisms of dampened inflammation in bats Geraldine Goha,1, Matae Ahna,1, Feng Zhua, Lim Beng Leea, Dahai Luob,c, Aaron T. Irvinga,d,2, and Lin-Fa Wanga,e,2 aProgramme in Emerging Infectious Diseases, Duke–National University of Singapore Medical School, 169857, Singapore; bLee Kong Chian School of Medicine, Nanyang Technological University, 636921, Singapore; cNTU Institute of Structural Biology, Nanyang Technological University, 636921, Singapore; dZhejiang University–University of Edinburgh Institute, Zhejiang University School of Medicine, Zhejiang University International Campus, Haining, 314400, China; and eSinghealth Duke–NUS Global Health Institute, 169857, Singapore Edited by Vishva M. Dixit, Genentech, San Francisco, CA, and approved September 14, 2020 (received for review February 21, 2020) Bats have emerged as unique mammalian vectors harboring a experimental confirmation is rare. We recently demonstrated diverse range of highly lethal zoonotic viruses with minimal that NLRP3 is dampened in bats as a result of loss-of-function clinical disease. Despite having sustained complete genomic loss bat-specific isoforms and impaired transcriptional priming (9). of AIM2, regulation of the downstream inflammasome response in The stimulator of IFN genes (STING), a key adaptor to the bats is unknown. AIM2 sensing of cytoplasmic DNA triggers ASC DNA-sensing cGAS protein, is also exclusively mutated at S358 aggregation and recruits caspase-1, the central inflammasome ef- in bats, resulting in a reduced IFN response to HSV1 (10). We fector enzyme, triggering cleavage of cytokines such as IL-1β and previously reported a complete absence of Absent in melanoma inducing GSDMD-mediated pyroptotic cell death. -
Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer
International Journal of Molecular Sciences Review Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer Zhaodi Zheng and Guorong Li * Shandong Provincial Key Laboratory of Animal Resistant, School of Life Sciences, Shandong Normal University, Jinan 250014, China; [email protected] * Correspondence: [email protected]; Tel.: +86-531-8618-2690 Received: 24 January 2020; Accepted: 17 February 2020; Published: 20 February 2020 Abstract: Programmed Cell Death (PCD) is considered to be a pathological form of cell death when mediated by an intracellular program and it balances cell death with survival of normal cells. Pyroptosis, a type of PCD, is induced by the inflammatory caspase cleavage of gasdermin D (GSDMD) and apoptotic caspase cleavage of gasdermin E (GSDME). This review aims to summarize the latest molecular mechanisms about pyroptosis mediated by pore-forming GSDMD and GSDME proteins that permeabilize plasma and mitochondrial membrane activating pyroptosis and apoptosis. We also discuss the potentiality of pyroptosis as a therapeutic target in human diseases. Blockade of pyroptosis by compounds can treat inflammatory disease and pyroptosis activation contributes to cancer therapy. Keywords: pyroptosis; GSDMD; GSDME; inflammatory disease; cancer therapy 1. Introduction Many disease states are cross-linked with cell death. The Nomenclature Committee on Cell Death make a series of recommendations to systematically classify cell death [1,2]. Programmed Cell Death (PCD) is mediated by specific cellular mechanisms and some signaling pathways are activated in these processes [3]. Apoptosis, autophagy and programmed necrosis are the three main types of PCD [4], and they may jointly determine the fate of malignant tumor cells. -
Emerging Role of PYHIN Proteins As Antiviral Restriction Factors
viruses Review Emerging Role of PYHIN Proteins as Antiviral Restriction Factors Matteo Bosso and Frank Kirchhoff * Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany; [email protected] * Correspondence: frank.kirchhoff@uni-ulm.de; Tel.: +49-731-50065150 Academic Editor: Sébastien Nisole Received: 26 November 2020; Accepted: 16 December 2020; Published: 18 December 2020 Abstract: Innate immune sensors and restriction factors are cellular proteins that synergize to build an effective first line of defense against viral infections. Innate sensors are usually constitutively expressed and capable of detecting pathogen-associated molecular patterns (PAMPs) via specific pattern recognition receptors (PRRs) to stimulate the immune response. Restriction factors are frequently upregulated by interferons (IFNs) and may inhibit viral pathogens at essentially any stage of their replication cycle. Members of the Pyrin and hematopoietic interferon-inducible nuclear (HIN) domain (PYHIN) family have initially been recognized as important sensors of foreign nucleic acids and activators of the inflammasome and the IFN response. Accumulating evidence shows, however, that at least three of the four members of the human PYHIN family restrict viral pathogens independently of viral sensing and innate immune activation. In this review, we provide an overview on the role of human PYHIN proteins in the innate antiviral immune defense and on viral countermeasures. Keywords: PYHIN; DNA sensing; restriction factors; viral counteraction; immune evasion 1. Introduction Viruses strictly rely on their host cells for replication and spread. However, although viral pathogens are capable of exploiting numerous cellular factors and pathways, the cell does not provide a friendly environment. As a consequence of countless past encounters with viral pathogens, mammalian cells have evolved sensors of foreign invaders that alert and activate a large variety of antiviral effector proteins [1–5]. -
A Member of the Pyrin Family, IFI16, Is a Novel BRCA1-Associated Protein Involved in the P53-Mediated Apoptosis Pathway
Oncogene (2003) 22, 8931–8938 & 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00 www.nature.com/onc A member of the Pyrin family, IFI16, is a novel BRCA1-associated protein involved in the p53-mediated apoptosis pathway Jason A Aglipay1, Sam W Lee2, Shinya Okada1, Nobuko Fujiuchi1, Takao Ohtsuka2, Jennifer C Kwak2, Yi Wang3,4, Ricky W Johnstone5, Chuxia Deng6, Jun Qin3,4 and Toru Ouchi*,1 1The Derald H. Ruttenberg Cancer Center, The Mount Sinai School of Medicine, New York University, New York, NY, USA; 2Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; 3Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA; 4Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA; 5Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Victoria, Australia; 6Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA We identified IFI16 as a BRCA1-associated protein C-terminal BRCT domains (Miki et al., 1994; Koonin involved in p53-mediated apoptosis. IFI16 contains the et al., 1996; Bork et al., 1997). Pyrin/PAAD/DAPIN domain, commonly found in cell Recently, mass-spectrometric analysis ofBRCA1- death-associated proteins. BRCA1 (aa 502–802) inter- interacting proteins revealed the presence of BRCA1- acted with the IFI16 Pyrin domain (aa 1–130). We found associated genome surveillance complex (BASC) (Wang that IFI16 was localized in the nucleoplasm and nucleoli. et al., 2000). This large complex includes ATM/ATR Clear nucleolar IFI16 localization was not observed in kinases, RAD51, MSH2, MSH6, MLH1, BLM and the HCC1937 BRCA1 mutant cells, but reintroduction of RAD50/Mre11/NBS complex, which are all involved in wild-type BRCA1 restored IFI16 nuclear relocalization homologous or nonhomologous recombination; coloca- following IR (ionizing radiation). -
The AIM2 Inflammasome: Sensor of Pathogens and Cellular Perturbations
The AIM2 Inflammasome: sensor of pathogens and cellular perturbations. Authors: Jérôme Lugrin1 Fabio Martinon2* Affiliations: 1Service of Adult Intensive Care Medicine, Lausanne University Hospital, Epalinges 1066, Switzerland. 2 Departement of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland. *Correspondence to: Fabio Martinon, Departement of Biochemistry University of Lausanne, Ch. Des Boveresses 155 Epalinges 1066, Switzerland Phone: +41-21-692.5695 Fax: +41-21-692.5705 Email: [email protected] Conflicts of interest statement: The author discloses no conflicts of interest. Running title: the AIM2 inflammasome Keywords: Inflammasomes, DNA sensors, Nuclear envelop stress, DNA damage, Innate Immunity Words count: 13245 Number of Figures: 4 1 Summary (250) Recognition of pathogens and altered self must be efficient and highly specific to orchestrate appropriate responses while limiting excessive inflammation and autoimmune reaction to normal self. AIM2 is a member of innate immune sensors that detects the presence of DNA, arguably the most conserved molecules in living organisms. However AIM2 achieve specificity by detecting altered or misslocalized DNA molecules. It can detect damaged DNA, and the aberrant presence of DNA within the cytosolic compartment such as genomic DNA released into the cytosol upon loss of nuclear envelope integrity. AIM2 is also a key sensor of pathogens that detects the presence of foreign DNA accumulating in the cytosol during the life cycle of intracellular pathogens including viruses, bacteria and parasites. AIM2 activation initiates the assembly of the inflammasome, an innate immune complex that leads to the activation of inflammatory caspases. This triggers the maturation and secretion of the cytokines IL-1β and IL-18. It can also initiate pyroptosis, a proinflammatory form of cell death. -
Gsdmd P30 Elicited by Caspase-11 During Pyroptosis Forms Pores in Membranes
GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes Robin A. Agliettia, Alberto Estevezb, Aaron Guptac, Monica Gonzalez Ramirezd, Peter S. Liue, Nobuhiko Kayagakic, Claudio Ciferrib, Vishva M. Dixitc,1, and Erin C. Duebera,1 aDepartment of Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA 94080; bDepartment of Structural Biology, Genentech, Inc., South San Francisco, CA 94080; cDepartment of Physiological Chemistry, Genentech, Inc., South San Francisco, CA 94080; dSanford-Burnham Medical Research Institute, La Jolla, CA 92037; and eDepartment of Protein Chemistry, Genentech, Inc., South San Francisco, CA 94080 Contributed by Vishva M. Dixit, May 27, 2016 (sent for review May 17, 2016; reviewed by Thirumala-Devi Kanneganti, Mohamed Lamkanfi, and Ruslan Medzhitov) Gasdermin-D (GsdmD) is a critical mediator of innate immune Results defense because its cleavage by the inflammatory caspases 1, 4, 5, Previous studies demonstrated that both endogenous and re- and 11 yields an N-terminal p30 fragment that induces pyroptosis, combinantly expressed mouse GsdmD were cleaved by caspase-11 a death program important for the elimination of intracellular (8, 9). We were also able to cleave recombinant human GsdmD with bacteria. Precisely how GsdmD p30 triggers pyroptosis has not a constitutively active form of caspase-11 lacking the N-terminal cas- been established. Here we show that human GsdmD p30 forms pase activation and recruitment domain (ΔCARDcasp-11; Fig. 1A). functional pores within membranes. When liberated from the The resulting N-terminal p30 domain precipitated after cleavage, corresponding C-terminal GsdmD p20 fragment in the presence of liposomes, GsdmD p30 localized to the lipid bilayer, whereas p20 whereas the C-terminal p20 domain was predominantly soluble B remained in the aqueous environment. -
Non-Apoptotic Cell Death Signaling Pathways in Melanoma
International Journal of Molecular Sciences Review Non-Apoptotic Cell Death Signaling Pathways in Melanoma Mariusz L. Hartman Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, Poland; [email protected]; Tel.: +48-42-272-57-03 Received: 10 April 2020; Accepted: 22 April 2020; Published: 23 April 2020 Abstract: Resisting cell death is a hallmark of cancer. Disturbances in the execution of cell death programs promote carcinogenesis and survival of cancer cells under unfavorable conditions, including exposition to anti-cancer therapies. Specific modalities of regulated cell death (RCD) have been classified based on different criteria, including morphological features, biochemical alterations and immunological consequences. Although melanoma cells are broadly equipped with the anti-apoptotic machinery and recurrent genetic alterations in the components of the RAS/RAF/MEK/ERK signaling markedly contribute to the pro-survival phenotype of melanoma, the roles of autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and parthanatos have recently gained great interest. These signaling cascades are involved in melanoma cell response and resistance to the therapeutics used in the clinic, including inhibitors of BRAFmut and MEK1/2, and immunotherapy. In addition, the relationships between sensitivity to non-apoptotic cell death routes and specific cell phenotypes have been demonstrated, suggesting that plasticity of melanoma cells can be exploited to modulate response of these cells to different cell death stimuli. In this review, the current knowledge on the non-apoptotic cell death signaling pathways in melanoma cell biology and response to anti-cancer drugs has been discussed. Keywords: autophagy; differentiation; drug resistance; ferroptosis; melanoma; necroptosis; parthanatos; pyroptosis; reactive oxygen species (ROS); targeted therapy 1. -
Distinct Regulatory Mechanisms Control Proinflammatory Cytokines IL-18 and IL-1Β
Cutting Edge: Distinct Regulatory Mechanisms Control Proinflammatory Cytokines IL-18 and IL-1β This information is current as Qifan Zhu and Thirumala-Devi Kanneganti of October 1, 2021. J Immunol published online 3 May 2017 http://www.jimmunol.org/content/early/2017/05/03/jimmun ol.1700352 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2017/05/03/jimmunol.170035 Material 2.DCSupplemental Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published May 3, 2017, doi:10.4049/jimmunol.1700352 Th eJournal of Cutting Edge Immunology Cutting Edge: Distinct Regulatory Mechanisms Control Proinflammatory Cytokines IL-18 and IL-1b Qifan Zhu*,† and Thirumala-Devi Kanneganti* Interleukin-18 and IL-1b, which are cytokines of the expressed in murine macrophages, dendritic cells, endothelial IL-1 family, are synthesized as precursor proteins and cells, intestinal epithelial cells, and keratinocytes under steady activated by the inflammasome via proteolytic process- state (8–10). -
Differential Roles for the Interferon-Inducible IFI16 and AIM2 Innate Immune Sensors for Cytosolic DNA in Cellular Senescence of Human Fibroblasts
Published OnlineFirst April 6, 2011; DOI: 10.1158/1541-7786.MCR-10-0565 Molecular Cancer Cell Cycle, Cell Death, and Senescence Research Differential Roles for the Interferon-Inducible IFI16 and AIM2 Innate Immune Sensors for Cytosolic DNA in Cellular Senescence of Human Fibroblasts Xin Duan1, Larissa Ponomareva1,2, Sudhakar Veeranki1, Ravichandran Panchanathan1, Eric Dickerson1,2, and Divaker Choubey1,2 Abstract The IFN-inducible IFI16 and AIM2 proteins act as innate immune sensors for cytosolic double-stranded DNA (dsDNA). On sensing dsDNA, the IFI16 protein induces the expression of IFN-b whereas the AIM2 protein forms an inflammasome, which promotes the secretion of IL-1b. Given that the knockdown of IFI16 expression in human diploid fibroblasts (HDF) delays the onset of cellular senescence, we investigated the potential roles for the IFI16 and AIM2 proteins in cellular senescence. We found that increased IFI16 protein levels in old (vs. young) HDFs were associated with the induction of IFN-b. In contrast, increased levels of the AIM2 protein in the senescent (vs. old) HDFs were associated with increased production of IL-1b. The knockdown of type I IFN-a receptor subunit, which reduced the basal levels of the IFI16 but not of the AIM2, protein delayed the onset of cellular senescence. Accordingly, increased constitutive levels of IFI16 and AIM2 proteins in ataxia telangiectasia mutated (ATM) HDFs were associated with the activation of the IFN signaling and increased levels of IL-1b. The IFN-b treatment of the young HDFs, which induced the expression of IFI16 and AIM2 proteins, activated a DNA damage response and also increased basal levels of IL-1b. -
AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury And
Published April 28, 2017, doi:10.4049/jimmunol.1600714 The Journal of Immunology AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality Hongbo Zhang,* Jiadi Luo,*,† John F. Alcorn,* Kong Chen,* Songqing Fan,*,† Joseph Pilewski,‡ Aizhong Liu,x Wei Chen,* Jay K. Kolls,* and Jieru Wang* The absent in melanoma 2 (AIM2) inflammasome plays an important role in many viral and bacterial infections, but very little is known about its role in RNA virus infection, including influenza A virus (IAV). In this study, we have designed in vivo and in vitro studies to determine the role of AIM2 in infections with lethal doses of IAVs A/PR8/34 and A/California/07/09. In wild-type mice, IAVinfection enhanced AIM2 expression, induced dsDNA release, and stimulated caspase-1 activation and release of cleaved IL-1b in the lung, which was significantly reduced in AIM2-deficient mice. Interestingly, AIM2 deficiency did not affect the transcription of caspase-1 and IL-1b. In addition, AIM2-deficient mice exhibited attenuated lung injury and significantly improved survival against IAV challenges, but did not alter viral burden in the lung. However, AIM2 deficiency did not seem to affect adaptive immune response against IAV infections. Furthermore, experiments with AIM2-specific small interfering RNA–treated and AIM2-deficient human and mouse lung alveolar macrophages and type II cells indicated a macrophage-specific function of AIM2 in regulation of IAV-stimulated proinflammatory response. Collectively, our results demonstrate that influenza infection activates the AIM2 inflammasome, which plays a critical role in IAV-induced lung injury and mortality.