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PROTEIN-PROTEIN INTERACTIONS with and WITHIN the NLRP3 INFLAMMASOME Evidence from STRING and Literature Studies

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PROTEIN-PROTEIN INTERACTIONS with and WITHIN the NLRP3 INFLAMMASOME Evidence from STRING and Literature Studies PROTEIN-PROTEIN INTERACTIONS WITH AND WITHIN THE NLRP3 INFLAMMASOME Evidence from STRING and literature studies Bachelor Degree Project in Bioscience G2E level, 30 ECTS Spring term 2020 Ralph Monte [email protected] Supervisor: Mikael Ejdebäck m [email protected] Examiner: Erik Gustafsson e [email protected] School of Bioscience University of Skövde Box 408 541 28 Skövde Abstract Inflammasomes are multiprotein complexes that play a role in the innate immune system. One inflammasome is the NLRP3 inflammasome, which can be activated and primed by different stimuli that bind to pattern recognition receptors (PRRs). There are many theories of how the NLRP3 inflammasome can be regulated, one of which is deubiquitination by deubiquitinating enzymes (DUBs). The NLRP3 inflammasome is also involved in many diseases, for example, diabetes, cancer and neurodegenerative diseases. The main aim of this study is to increase knowledge of the protein-protein interactions with and within the NLRP3 inflammasome. Thus, this study will give further insight into NLRP3 inflammasome pathways and can lead to novel treatment targets for different NLRP3-associated diseases in the future. The NLRP3 inflammasome and its regulation were described in this study and protein-protein interaction (PPI) networks of the individual NLRP3 inflammasome key components (NLRP3, PYCARD, caspase-1) were obtained from STRING for human, mouse and macaque orthologs. The obtained PPI networks were then compared. The types of PPI in all PPI networks, either functional or physical, were verified by KEGG or research literature, respectively. Mass spectrometry data of unstimulated and stimulated THP-1 cells were also analyzed. During this study the BRISC complex and its members, a DUB, was also further explored. All in all, the study increased the knowledge about the protein-protein interactions with and within the NLRP3 inflammasome. Further research can aid in the discovery of novel treatment targets of diseases related to inflammasomes. List of abbreviations CASP1 Caspase-1 Co-IP Co-immunoprecipitation DAMP Damage-associated molecular pattern DSB Double strand break DUB Deubiquitinating enzyme IL Interleukin KEGG Kyoto Encyclopedia of Genes and Genomes LPS Lipopolysaccharide MS Mass spectrometry NLRP3 Nod-like receptor 3 PAMP Pathogen-associated molecular pattern PPI Protein-protein interaction PYCARD Pyrin-containing CARD domain STRING Search Tool for the Retrieval of Interacting Genes/Proteins Table of Contents Introduction .........................................................................................................................................................................1 Methods ..................................................................................................................................................................................5 Results ....................................................................................................................................................................................6 Discussion .......................................................................................................................................................................... 21 Conclusion and future perspectives ........................................................................................................................ 23 Acknowledgements ........................................................................................................................................................ 24 References .......................................................................................................................................................................... 25 Appendix 1 – Schematic NLRP3 inflammasome construction reaction ................................................... 32 Appendix 2 – MS data analysis .................................................................................................................................. 33 Introduction The immune system is a system to protect from pathogens and other harmful substances. There are two types of immunity: innate immunity and adaptive immunity (Iwasaki & Medzhitov, 2015). Innate immunity is the first line of defense and consists of mechanical barriers, like the skin, and cellular components and processes. After the initial response of the innate immunity, the adaptive immunity is triggered. Adaptive immunity, also called acquired immunity, is a system with an immunological memory that includes specialized cells: T cells and B cells (Bonilla & Oettgen, 2010). The T cells are activated by antigen-presenting macrophages. Subsequently, T cells activate killer cells, which phagocytize the pathogen. The B cells are also activated and either become plasma cells that produce antibodies that suppress the foreign antigen or they become memory cells. One part of the innate immune system against harmful substances is inflammation. Inflammation is characterized by heat (calor), pain (dolor), rubor (redness), swelling (tumor) and function loss (fuctio laesia) as described by Calsus and Galen. There are two major types of inflammation. Acute inflammation is inflammation that lasts a relatively short time and chronic inflammation can last for months or even years (Pahwa, Goyal, Bansal & Jialal, 2020). Acute inflammation follows some basic steps (Medzhitov, 2008). After exposure to pathogens, or due to tissue or cellular damage, plasma and leukocytes are delivered to the area of injury or infection. Mast cells then produce inflammatory biomolecules, including cytokines that signal for vasodilation, which leads to transport of plasma and leukocytes to the area of injury or infection. This is called leukocyte extravasation (Vestweber, 2015). Exits of red blood cells from the area of injury are also blocked. Subsequently, the neutrophils are activated directly or indirectly, i.e. by cytokines. Finally, the activated neutrophils kill the pathogen by producing granules, which contain components that can lyse the pathogen (Brostjan & Oehler, 2020). Injury or infection also activate inflammasomes. Inflammasomes are multiprotein complexes that are components of the innate immune system (Martinon, Burns & Tschopp, 2002). Inflammasomes contain pro-caspases, which are activated and are important in inflammation. Inflammasomes cause pyroptosis upon activation. Pyroptosis was first defined as inflammatory caspase-mediated cell death (Man, Karki & Kanneganti, 2017). However, recent discoveries have changed the definition to gasdermin D (GSDMD)-mediated cell death instead (Shi, Gao & Shao, 2017). Pyroptosis is activated by either damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs). These patterns are recognized by transmembrane proteins, like toll-like receptors (TLRs) or cytoplasmic receptors. The transmembrane and cytoplasmic receptors are collectively called pattern recognition receptors (PRRs) (Takeuchi & Akira, 2010). The NLRP1 inflammasome is part of the NLR family of inflammasomes and was the first inflammasome discovered and described in the scientific article of Martinon, Burns and Tschopp (2002). There are different types of inflammasomes known, including NLRP1 (Nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR)-containing (NLR) family pyrin domain containing 1), NLRP3, NLRC4, absent in melanoma 2 (AIM2) and Pyrin. These are the canonical inflammasomes. Furthermore, there are also non-canonical inflammasomes. All of the previously mentioned inflammasomes differ in molecular structure and in activation (Rathinam & Fitzgerald, 2016). The focus will be on the related NLRP3 inflammasome. NLRP3 inflammasome Just like NLRP1, the NLRP3 inflammasome is part of the NLR family of inflammasomes. There is a consensus that there is a two-step activation: a priming signal and an activation signal needed to construct an active inflammasome (He, Hara & Núñez, 2016). First, the priming signal originates Page: 1 from binding of different stimuli to the PRRs. The signaling activates nuclear factor kappa B (NF- -IL- -IL18 and NLRP3 transcripts amongst others. An overview of the different PAMP signals that cause the priming signalκB), which can be is founda transcription in Table 1. factor and increased synthesis of pro 1β, pro Table 1. PAMP signals that cause the NLRP3 priming signal Stimuli Research paper Nigericin Perregaux & Gabel (1994) Maitotoxin Mariathesan et al. (2006) Viruses, e.g. influenza A Ichinohe, Pang & Iwasaki (2010) Bacteria, e.g. Staphylococcus aureus McGillan et al. (2013) LPS Kayagaki et al. (2013) The second signal is activation. The activation step activates the inflammasome, can be triggered by numerous, structurally different stimuli, the DAMP stimuli (Place & Kanneganti, 2020). There is no general consensus of the exact mechanism of activation. An overview of DAMP stimuli and connected research papers are listed in Table 1. Table 2. DAMP stimuli that affect NLRP3 activation Stimuli Research paper Silica Hornung et al. (2008) Pathogen-driven ligands, e.g. pore-forming toxins Endogenous danger signals, e.g. serum amyloid A, Mariathasan et al. (2006) ATP K+ efflux Pétrilli et al. (2007) Lysosomal disturbance Wang, Yuan, Chen & Wang (2019) Signaling by calcium Lee et al. (2012) Mitochondria-derived factors, e.g. oxidized Shimada et al. (2012) mitochondrial DNA Reactive oxygen species and cardioplin Pétrilli, Dostert, Muruve, & Tschopp (2007) Microtubule-driven
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