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BL9412 Public Health Question: Discuss the expanding roles of ubiquitin-like molecules in the innate immune response to infection. Answer: Introduction: Innate immunity is determined as the first line of the defence contrary to various microbial infection. The pattern recognition receptors (PRRs) sense the pathogen-associated molecular patterns (PAMPs) and trigger the immediate host response against infections. Gradually the chemokine and the cytokines are secreted to initiate the adaptive immunity (Jiang & Chen, 2011). Many critical signalling proteins have been featured to mediate the PRR signalling pathway. A large number of resources, proves that the these signalling proteins are modulated by the post-translational modification of the proteins (acetylation, Ubiquitination, SUMOylation and ISGylation) This paper will provide a literature review to determine the role of the Ubiquitin like molecules in the innate immune responses in infection. Literature Review  Ubiquitination can be referred to as an energy host defence dependant, after the translational modification process in which the 8kDa ubiquitin protein is attached covalently to one of the more lysine residues of a substrate protein. Ubiquitination is a method that consists of three events – the activation, conjugation and ligation, involves the three different types of the coenzymes- the initial step is considered as ATP dependant and is carried out by the ubiquitin activating enzyme (Jiang & Chen, 2011). The process of ubiquitylation regulates several biological processes including the immune responses. The role of the ubiquitin like molecules in the regulation of the immune system was uncovered by the studies of the antigen presentation and the nuclear factor factor-κB of the transcription factors that plays an important role in the host defence against the microorganisms. Regulation Process Of The Innate Immunity By The Ubiquitylation Right after the introduction to the pathogens, the immune system identifies the pathogen associated molecular patterns (PAMPs) with the help of the germ line encoded pattern recognition receptors (PRRs), like the Toll-like receptors (TLRs), the RIG-I- like receptors (RLS) and the NOD like receptors  (NLRs) (Jiang & Chen, 2011). The signalling receptors emanating from these receptors triggers the activation of the transcription factors, including those belonging to the nuclear factor-κB (NF-κB) and the interferon regulatory factor (IRF) families. These transcription factors afterwards coordinate the gene expression process that helps in protecting the cells and the organs from pathogenic infection. Some of the genes  which are induced by the NF-κB and IRFs encodes the pro-inflammatory cytokines and the type I interferons (IFNs), that directly does not supress the infections created by microbes but also helps in the activation of the adaptive immune system for ultimately destroying the pathogens (Oudshoorn,  Versteeg & Kikkert, 2012). After the discovery of Ubiquitin, Ubiquitin-like modifiers have been identified. Ubiquitin like modifiers such as ISG15 and SUMO shows limited sequence homology with the ubiquitin , but share conserved structural characteristics like the Ubiquitin folds and the presence of one or two C-terminal glycine for the conjugation (Oudshoorn,  Versteeg & Kikkert, 2012). A consensus sequence in the substrates (ψKXE), is required in the SUMOylation, where ψ is the hydrophobic residue and X is any amino acid. ISG15 is also a potential antiviral molecule that is produced after the signalling of the interferon. It is normally conjugated to newly synthesised proteins for inhibiting the viral replication (Oudshoorn,  Versteeg & Kikkert, 2012). Cytotoxic CD8 T-cells are necessary for the tumour control but insufficient generation of the Cd8 effector cells is still a problem.  ISG15 is an ubiquitin like protein that is induced by type I interferon related to the antiviral activity (Villarreal et al., 2015). It is known to be functioning as an immunomodulatory molecule. ISGI5 has been found to be acting as a vaccine adjuvant that induces human papilloma virus (HPV) E7-specific IFNγ responses and effector CD8-T cell responses (Villarreal et al., 2015). Using of ISG15 as a vaccine has been found to be having a remarkable effect in the mice with HPV associated tumour. This protective efficacy of ISG15 is CD8 cell mediated which has been found by the depletion of T-cell coupled with adoptive transfer experiments. Role Of The Ubiquitin Like Molecule In The TLR Signalling They are families of membrane bound receptors that are responsible for sensing a broad number of pathogens including, fungi, bacteria, protests and the viruses (Zinngrebe et al., 2013). The TLR activity can be categorised in to two main adaptor proteins- TIR domain comprising adaptor protein inducing IFNβ (TRIF) and myeloid differentiation primary response protein 88 (MYD88) and adaptor proteins containing TLR domains inducing IFNβ (TRIF) (Kawasaki & Kawai, 2014). MYD88-dependent pathways used by all the TLRs and the TRIF-dependent pathway that transmits the signals from the TLR3 leading to the introduction of both the type I IFNs and the pro-inflammatory cytokines (Tseng et al., 2010). MyD88 is also necessary for the production of the type 1 interferon induced by the TLR7/9 (Zinngrebe et al., 2013). The Ubiquitylation is also involved in the activation of the mitogen activated protein kinase (MAPK) cascade situated downstream of both the MYD88 and the TRIF dependant pathways. The IRAK4 phosphorylates and activates the IRAK-1 that dissociates the IRAKs from the MYD88 and interacts with ubiquitin ligase. The ubiquitin ligase along with the Ubc 13 and the Uev 1A catalyses the formation of the poly-ubiquitin chains activating the downstream kinase complex (Kawasaki & Kawai, 2014). The poly-ubiquitin chains acts as the attachment platform for the TAK complexes and the IKK complex leading to the activation and the induction of the pro-inflammatory cytokines.  The polyubiquitin chain recruits the protein complexes which ultimately leads to the induction of the type I IFNs and the ISGs (Interferon inducible genes). Furthermore the protein kinases are also activated by the non- K48 linked polyubiquitin chains. Role Of Ub And Ubls In The NLR Signalling Pathway The Nucleotide binding domains helps to sense the presence of bacterial peptidoglycan components. The member of the Nod- like receptors (NLR) family develops immune response by activating the NF-κB and the creation of the caspase-1-activating inflammasomes (Liu et al., 2013).  Non-degradative polyubiquitination is needed for the well-organized initiation of the NF-κB activation and maturation of caspase-1 (Correa et al., 2012).   Role Of The Ubls In The RLRs Signalling On contrary with the TLRs, which helps to screen the occurrence of a topologically extracellular viruses within the immune cells, the RNA helicases RIG-I (retinoic acid inducible gene I, also known as Ddx58) and Mda5 (melanoma differentiation-associated gene 5) that have been detected to be a ubiquitous sensor for the detection of cytosolic RNA viruses at the time of the primary host response (Liu et al., 2013). After an infection with any RNA virus, the RIG-I/MDA5 binds to the double stranded RNAs and undergoes some changes in the conformation. Connotation with the adaptor protein MAVS takes place that triggers the recruitment of the other signal transduction proteins such as Tom70, TRAF3 and TBK1 (Kato et al., 2016).  The transcription factor IRF3 is phosphorylated by the activation of the TBK1n which then translocate in to the nucleus for initiating the antiviral gene transcription (Liu et al., 2010). Conclusion: In conclusion it can be said that Ubiquitin have been characterised extensively as the versatile mechanism for the elimination of the microbes. The ubiquitin like proteins or the molecules are emerging as novel means for the modulation of the signals. Importantly, this literature review, helps to find out the gap in this research field, as of the way Ubiquitination, ISGylation, and SUMOylation act synergistically and the implications of the different linkages in the process of ubiquitination. Hence, there are more works and processing are necessary to understand the regulatory processes associated in the removal of the Ub and the Ubls in the physiological contexts of the process. References: Correa, R. G., Milutinovic, S., & Reed, J. C. (2012). Roles of NOD1 (NLRC1) and NOD2 (NLRC2) in innate immunity and inflammatory diseases. Bioscience reports, 32(6), 597-608. Jiang, X., & Chen, Z. J. (2011). The role of ubiquitylation in immune defence and pathogen evasion. Nature reviews. Immunology, 12(1), 35-48. doi:10.1038/nri3111  Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., … & Yamaguchi, O. (2016). Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature, 441(7089), 101. Kawasaki, T., & Kawai, T. (2014). Toll-like receptor signaling pathways. Frontiers in immunology, 5, 461. Liu, X. Y., Wei, B., Shi, H. X., Shan, Y. F., & Wang, C. (2010). Tom70 mediates activation of interferon regulatory factor 3 on mitochondria. Cell research, 20(9), 994.  Liu, X., Wang, Q., Chen, W., & Wang, C. (2013). Dynamic regulation of innate immunity by ubiquitin and ubiquitin-like proteins. Cytokine & growth factor reviews, 24(6), 559-570. Oudshoorn, D., Versteeg, G. A., & Kikkert, M. (2012). Regulation of the innate immune system by ubiquitin and ubiquitin-like modifiers. Cytokine & growth factor reviews, 23(6), 273-282. Tseng, P. H., Matsuzawa, A., Zhang, W., Mino, T., Vignali, D. A., & Karin, M. (2010). Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nature immunology, 11(1), 70. Villarreal, D. O., Wise, M. C., Siefert, R. J., Yan, J., Wood, L. M., & Weiner, D. B. (2015). Ubiquitin-like Molecule ISG15 Acts as an Immune Adjuvant to Enhance Antigen-specific CD8 T-cell Tumor Immunity. Molecular therapy : the journal of the American Society of Gene Therapy, 23(10), 1653-62. Zinngrebe, J., Montinaro, A., Peltzer, N., & Walczak, H. (2013). Ubiquitin in the immune system. EMBO reports, 15(1), 28-45.

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