Inflammation Drives Alternative First Exon Usage to Regulate Immune Genes Including A
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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). -
AIM2 Inflammasome Is Activated by Pharmacological Disruption Of
AIM2 inflammasome is activated by pharmacological PNAS PLUS disruption of nuclear envelope integrity Antonia Di Miccoa,1, Gianluca Freraa,1,JérômeLugrina,1, Yvan Jamillouxa,b,Erh-TingHsuc,AubryTardivela, Aude De Gassarta, Léa Zaffalona, Bojan Bujisica, Stefanie Siegertd, Manfredo Quadronie, Petr Brozf, Thomas Henryb,ChristineA.Hrycynac,g, and Fabio Martinona,2 aDepartment of Biochemistry, University of Lausanne, Epalinges 1066, Switzerland; bINSERM, U1111, Center for Infectiology Research, Lyon 69007, France; cDepartment of Chemistry, Purdue University, West Lafayette, IN 47907-2084; dFlow Cytometry Facility, Ludwig Center for Cancer Research, University of Lausanne, Epalinges 1066, Switzerland; eProtein Analysis Facility, Center for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland; fFocal Area Infection Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland; and gPurdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907-2084 Edited by Zhijian J. Chen, University of Texas Southwestern Medical Center/Howard Hughes Medical Institute, Dallas, TX, and approved June 21, 2016 (received for review February 12, 2016) Inflammasomes are critical sensors that convey cellular stress and and in vitro (19, 20). Beyond their broad use as anti-HIV drugs, pathogen presence to the immune system by activating inflamma- these molecules display beneficial HIV-unrelated functions, anti- tory caspases and cytokines such as IL-1β. The nature of endogenous malaria, antituberculosis, and antitumor properties (20). At the stress signals that activate inflammasomes remains unclear. Here cellular level, the HIV-PIs trigger an atypical ER stress-like we show that an inhibitor of the HIV aspartyl protease, Nelfinavir, transcriptional response that relies mostly on the activation of the triggers inflammasome formation and elicits an IL-1R–dependent integrated stress response (19, 21). -
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. -
Long Non-Coding RNA Landscape in Prostate Cancer Molecular Subtypes: a Feature Selection Approach
International Journal of Molecular Sciences Article Long Non-Coding RNA Landscape in Prostate Cancer Molecular Subtypes: A Feature Selection Approach Simona De Summa 1,* , Antonio Palazzo 2 , Mariapia Caputo 1, Rosa Maria Iacobazzi 3 , Brunella Pilato 1, Letizia Porcelli 3, Stefania Tommasi 1 , Angelo Virgilio Paradiso 4,† and Amalia Azzariti 3,† 1 Molecular Diagnostics and Pharmacogenetics Unit, IRCCS IstitutoTumori Giovanni Paolo II, 70124 Bari, Italy; [email protected] (M.C.); [email protected] (B.P.); [email protected] (S.T.) 2 Laboratory of Nanotechnology, IRCCS IstitutoTumori Giovanni Paolo II, 70124 Bari, Italy; [email protected] 3 Laboratory of Experimental Pharmacology, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy; [email protected] (R.M.I.); [email protected] (L.P.); [email protected] (A.A.) 4 Scientific Directorate, IRCCS Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy; [email protected] * Correspondence: [email protected] † Co-senior authors. Abstract: Prostate cancer is one of the most common malignancies in men. It is characterized by a high molecular genomic heterogeneity and, thus, molecular subtypes, that, to date, have not been used in clinical practice. In the present paper, we aimed to better stratify prostate cancer patients through the selection of robust long non-coding RNAs. To fulfill the purpose of the study, a bioinformatic approach focused on feature selection applied to a TCGA dataset was used. In such a way, LINC00668 and long non-coding(lnc)-SAYSD1-1, able to discriminate ERG/not-ERG subtypes, Citation: De Summa, S.; Palazzo, A.; were demonstrated to be positive prognostic biomarkers in ERG-positive patients. -
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. -
A Genomics Approach Reveals Insights Into the Importance of Gene Losses for Mammalian Adaptations
Corrected: Publisher correction ARTICLE DOI: 10.1038/s41467-018-03667-1 OPEN A genomics approach reveals insights into the importance of gene losses for mammalian adaptations Virag Sharma1,2,3, Nikolai Hecker1,2,3, Juliana G. Roscito1,2,3, Leo Foerster1,2,3, Bjoern E. Langer1,2,3 & Michael Hiller1,2,3 1234567890():,; Identifying the genomic changes that underlie phenotypic adaptations is a key challenge in evolutionary biology and genomics. Loss of protein-coding genes is one type of genomic change with the potential to affect phenotypic evolution. Here, we develop a genomics approach to accurately detect gene losses and investigate their importance for adaptive evolution in mammals. We discover a number of gene losses that likely contributed to morphological, physiological, and metabolic adaptations in aquatic and flying mammals. These gene losses shed light on possible molecular and cellular mechanisms that underlie these adaptive phenotypes. In addition, we show that gene loss events that occur as a consequence of relaxed selection following adaptation provide novel insights into species’ biology. Our results suggest that gene loss is an evolutionary mechanism for adaptation that may be more widespread than previously anticipated. Hence, investigating gene losses has great potential to reveal the genomic basis underlying macroevolutionary changes. 1 Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstr. 108, 01307 Dresden, Germany. 2 Max Planck Institute for the Physics of Complex Systems, Noethnitzer Str. 38, 01187 Dresden, Germany. 3 Center for Systems Biology Dresden, Pfotenhauerstr. 108, 01307 Dresden, Germany. Correspondence and requests for materials should be addressed to M.H. (email: [email protected]) NATURE COMMUNICATIONS | (2018) 9:1215 | DOI: 10.1038/s41467-018-03667-1 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-03667-1 ne of the most fascinating aspects of nature is the a b % conserved genes diversity of life. -
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]. -
Array Painting Reveals a High Frequency of Balanced Translocations in Breast Cancer Cell Lines That Break in Cancer-Relevant Genes
Oncogene (2008) 27, 3345–3359 & 2008 Nature Publishing Group All rights reserved 0950-9232/08 $30.00 www.nature.com/onc ONCOGENOMICS Array painting reveals a high frequency of balanced translocations in breast cancer cell lines that break in cancer-relevant genes KD Howarth1, KA Blood1,BLNg2, JC Beavis1, Y Chua1, SL Cooke1, S Raby1, K Ichimura3, VP Collins3, NP Carter2 and PAW Edwards1 1Department of Pathology, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK; 2Wellcome Trust Sanger Institute, Cambridge, UK and 3Department of Pathology, Division of Molecular Histopathology, Addenbrookes Hospital, University of Cambridge, Cambridge, UK Chromosome translocations in the common epithelial tion and inversion, which can result in gene fusion, cancers are abundant, yet little is known about them. promoter insertion or gene inactivation. As is well They have been thought to be almost all unbalanced and known in haematopoietic tumours and sarcomas, therefore dismissed as mostly mediating tumour suppres- translocations and inversions can have powerful onco- sor loss. We present a comprehensive analysis by array genic effects on specific genes and play a central role in painting of the chromosome translocations of breast cancer development (Rowley, 1998). In the past there cancer cell lines HCC1806, HCC1187 and ZR-75-30. In has been an implicit assumption that such rearrange- array painting, chromosomes are isolated by flow ments are not significant players in the common cytometry, amplified and hybridized to DNA microarrays. epithelial -
Supplementary Information
Supplementary Information A genomics approach reveals insights into the importance of gene losses for mammalian adaptations Sharma et al. The Supplementary Information contains - Supplementary Figures 1 - 35 - Supplementary Tables 1 - 8 - Supplementary Notes 1 - 8 1 A reference species with B annotated functional genes ? ? ? ? ? ? use Dollo parsimony ? ? to infer gene ancestry ? search for gene losses reference ? in query species ? ? ? ? ? non-ancestral branches Supplementary Figure 1: General framework for detecting gene losses in genome alignments. (A) Our approach considers all coding genes that are annotated and thus likely functional in a chosen reference species. We detect loss of a given gene in other query species by searching genome alignments for gene-inactivating mutations. Genome alignments are well-suited to detect gene losses for the following reasons. First, genome alignments can reveal the remnants of inactivated but not completely deleted genes, even if these genes are not expressed anymore and thus are not contained in a transcriptome or in mRNA/protein databases. Second, splice site mutations, which are one important class of inactivating mutations, can only be detected at the genomic but not at the mRNA/protein level. Third, information about missing sequence (assembly gaps, regions of low sequencing quality) are only visible by direct genome analysis. This is important as the absence of a gene in a gene/protein database or in a genomic BLAST run cannot distinguish between artifacts that perfectly mimic absence of a gene (such as large assembly gaps) and the complete deletion of a gene. Since gene loss in a query species requires that the common ancestor of the reference and this query species possessed the gene, we used Dollo parsimony to infer gene ancestry based on query species where the gene lacks any gene-inactivating mutations. -
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.