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  • br Conclusion br Introduction br CRL E ligases


    CRL4 E3 ligases in tumorigenesis
    Small molecule-based PROTACs
    PROTAC: Major biological impacts
    Acknowledgements The authors sincerely apologize to all those colleagues whose important work was not cited in this paper owing to space limitations. They thank the members of Wei laboratory for critical reading and discussion of the manuscript. W.W. is a Leukemia & Lymphoma Society (LLS) research scholar. This work was supported in part by Scientific Research Training Program for Young Talents (Union Hospital, Tongji Medical College, Huazhong University of Science and Technology) to J.C., by National Natural Science Foundation of China (81572413) to K.T., by the V Foundation for Cancer Research to P.Z., and by US National Institutes of Health (NIH) grants to P. Z. (CA159925 and CA213992) and W.W. (GM094777 and CA177910).
    Introduction The first step in innate immunity signaling is the recognition of PAMPs by their corresponding PRRs. The signature PAMPs in viruses are the viral nucleic acids including double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), and dsDNA [1]. The viral PAMPs are mainly recognized by three kinds of PRRs, including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and cytosolic DNA sensors (CDSs) such as cyclic GMP-AMP synthase (cGAS). TLRs are the membrane-bound PRRs, while RLRs and CDSs belong to the cytoplasmic PRRs.Fig 1.Table 1. The interaction between the PAMPs and the PRRs initiates the signal transduction cascade. The receptors perceive viral nucleic acids, resulting in the recruitment and activation of the adaptor protein including Toll/interleukin-1 receptor domain-containing adaptor protein inducing interferon beta (TRIF) [2], myeloid differentiation factor-88 (MyD88) [3], mitochondrial antiviral signaling protein (MAVS) [4], and stimulator of interferon genes protein (STING) [5], respectively. The adaptor proteins act as a scaffold, recruiting and activating the kinases including inhibitor of nuclear factor kappa-B [IκB] kinase (IKK) family and TANK-binding kinase-1 (TBK1). Furthermore, IKK family and TBK1 are responsible for the activation of transcription factors nuclear factor kappa-light-chain-enhancer of activated GSK2636771 (NF-κB) and interferon-regulatory factor 3 (IRF3), respectively. IKK family, including IKKα, IKKβ, and IKKγ (NEMO), phosphorylates IκBα and leads to its ubiquitination and proteasomal degradation, which releases the sequestered NF-κB (p65/p50) and leads to its translocation from cytoplasm to the nucleus [6]. The translocated NF-κB is then engaged in the production of the proinflammatory cytokines. TBK1 cooperates with IKK-related kinase IKKε to phosphorylate and activate IRF3, leading to its dimerization and translocation. The translocated IRF3 mediates the induction of the genes encoding type I IFNs and IFN regulatory factors in the nucleus [7]. Ubiquitin is an 8.5 kDa protein composed of 76 amino acids. The addition of ubiquitin to a substrate protein is called ubiquitination, which is completed through three distinct classes of enzymes: ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s) [8]. Since there are limited numbers of E1 and E2 enzymes, the substrate specificity relies mainly on the E3 ubiquitin ligase. E3s are divided into three types according to their domain structure, HECT (homologous to E6-associated protein C-terminus), RING (Really Interesting New Gene), and RBR (RING-IBR-RING) [9]. HECT type E3s contain HECT domain at their C terminus, while the RING E3s are characterized by their RING or U-box fold catalytic domain. Different from both of them, RBR E3s are defined by a homologous sequence, encompassing two predicted RING fingers (RING1 and RING2) and a central in-between-RINGs (IBR) zinc-binding domain [9]. Conjugation of ubiquitin to substrates occurs at lysine residues of the substrate proteins. Lysine residues of the substrate can be modified with a single ubiquitin moiety (monoubiquitination) or chains of ubiquitin (polyubiquitination). Polyubiquitin chains are formed through the covalent binding of C-terminal glycine of one ubiquitin molecule with the lysine or methionine of another ubiquitin molecule [8]. Ubiquitin itself contains eight amino groups for another ubiquitin molecule to conjugate with: the ε-amino groups of seven lysine residues (K6, 11, 27, 29, 33, 48, and 63) and the α-amino group of the N-terminal methionine residue. Among them, the K48- and K63-linked polymeric chains are the best described. K48-based polyubiquitin chains are the canonical signal to target protein for the proteasome-dependent degradation, while K63-based chains regulate signal transduction, protein endocytosis, trafficking, and enzymatic activity [10]. There are emerging studies suggesting the involvement of atypical types of ubiquitin chains in innate immunity [10]. For example, M1-linked chains, which are catalyzed by a linear ubiquitin chain assembly complex (LUBAC), are essential for the NF-κB activation and regulation of IFN production [11], [12]. Besides M1-linked chains, K11-, K27-, K-29 polyubiquitin chains are also suggested to play role in the modulation of innate immunity.