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CORD-19:f2331a5c6268ec47649983001535019aff087c35 JSONTXT 7 Projects

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Id Subject Object Predicate Lexical cue
T1 0-79 Sentence denotes Inhibition of IRF3-dependent antiviral responses by cellular and viral proteins
T2 81-181 Sentence denotes The host evokes innate immune responses to eliminate viruses by detecting the presence of infection.
T3 182-403 Sentence denotes Host cells respond to nucleic acids derived from infected viruses to produce cytokines known as type I interferons (IFNb and multiple IFNa), which are the most important cytokines for host defense against viral infection.
T4 404-823 Sentence denotes Type I interferons induce the synthesis of hundreds of IFN-inducible genes (ISG) that influence protein synthesis, growth arrest and cell death to induce the antiviral state as well as enhance dendritic cell maturation, natural killer cell activation, antibody production and differentiation of virus-specific cytotoxic T lymphocytes, which coordinately lead to the establishment of antiviral adaptive immune responses.
T5 824-1046 Sentence denotes Innate immune detection of virus infection is mediated by host pattern recognition receptors (PRRs), including RNA helicases RIG-I and MDA5 and several members of Toll-like receptors (TLR) such as TLR3, TLR7 and TLR9 [1] .
T6 1047-1210 Sentence denotes Of these, RIG-I, MDA5 and TLR3 function as sensors of double stranded RNA species that are produced by many viruses during replication, and trigger IFNb induction.
T7 1211-1503 Sentence denotes Transcription of the IFNb gene requires the assembly of three distinct families of transcription factors, including NF-kB, ATF2/c-Jun and IRF3, to the positive regulatory domains (PRD) in the promoter region; and signals by RIG-I/MDA5 and TLR3 activate these three transcription factors [2] .
T8 1504-1583 Sentence denotes Of these, IRF3 plays a critical role in the initial induction of the IFNb gene.
T9 1584-1881 Sentence denotes IRF3 is a constitutively expressed protein that resides in the cytoplasm in unstimulated cells, but virus infection triggers IRF3 phosphorylation at serine/ threoine clusters in the C-terminal regulatory regions, which allows IRF3 to form a homodimer, translocate into the nucleus and bind to DNA.
T10 1882-2050 Sentence denotes RIG-I/MDA5 and TLR3 signaling pathways converge on a common TRAF3 adapter complex, which then activates two protein kinases TBK1 and IKKi that function as IRF3 kinases.
T11 2051-2185 Sentence denotes Conjugation of proteins by ubiquitin is fundamentally important in various cellular processes, including innate immune signaling [3] .
T12 2186-2284 Sentence denotes Ubiquitin contains seven lysine residues that could mediate the formation of polyubiquitin chains.
T13 2285-2565 Sentence denotes Lysine 48 (K48)-linked polyubiquitination typically targets proteins for degradation by the ubiquitin-proteasome pathway while K63-linked polyubiquitination modulates protein-protein interactions and protein cellular localization to influence the activation of signaling pathways.
T14 2566-2705 Sentence denotes Moreover, cellular deubiquitinating (DUB) enzymes catalyze the removal of polyubiquitin chains to counteract the effects of ubiquitination.
T15 2706-2957 Sentence denotes Two studies by Zheng et al. and Zhang et al. in a recent issue of Cell Research identified new cellular and viral proteins, both of which negatively regulate type I IFN induction by modulating IRF3 ubiquitination but with different mechanisms [4, 5] .
T16 2958-3183 Sentence denotes The study of Zhang et al. demonstrated that the E3 ubiquitin ligase RBCC protein interacting with PKC1 (RBCK1) binds to IRF3 and targets it for ubiquitination and subsequent degradation through a proteasome-dependent pathway.
T17 3184-3342 Sentence denotes Consistently, overexpression of RBCK1 suppressed Sendai virusinduced type I IFN induction, while knockdown of RBCK1 resulted in enhanced type I IFN induction.
T18 3343-3483 Sentence denotes Notably, they found that Sendai virus infection increased the level of RBCK1 expression, which was accompanied by a decrease in IRF3 levels.
T19 3484-3613 Sentence denotes They therefore concluded that RBCK1-mediated IRF3 degradation is important for termination of IRF3-dependent antiviral responses.
T20 3614-3803 Sentence denotes Although type I IFN is required for elimination of viruses, aberrant type I IFN production contributes to the development of autoimmune disorders, such as systemic lupus erythematosus [6] .
T21 3804-3901 Sentence denotes Thus, mechanisms that suppress the production of type I IFN are critical to maintain homeostasis.
T22 3902-3993 Sentence denotes Several cellular factors have been suggested to participate in negative regulation of IRF3.
T23 3994-4075 Sentence denotes These include cytoplasmic peptidyl-prolyl-isomerase Pin1 and Ro52/TRIM21 [7, 8] .
T24 4076-4164 Sentence denotes Pin1 binds phosphorylated IRF3 to trigger its ubiquitination and subsequent degradation.
T25 4165-4265 Sentence denotes However, unlike RBCK1, PIN1 expression is constitutive and it interacts with IRF3 after stimulation.
T26 4266-4362 Sentence denotes Whereas PIN1 does not affect NF-κB activation, RBCK1 has a role in suppressing NF-kB activation.
T27 4363-4475 Sentence denotes These findings suggest that RBCK1 plays a broader role in the suppression of host antiviral responses than PIN1.
T28 4476-4670 Sentence denotes Ro52/ TRIM21, which is an inducible protein and an autoantigen present in patients with systemic lupus erythematosus and Sjögren's syndrome, also targets IRF3 for ubiquitination and degradation.
T29 4671-4800 Sentence denotes However, it also interacts with other IRFs such as IRF7 and IRF8, in contrast to RBCK1 that specifically binds IRF3 but not IRF7.
T30 4801-4939 Sentence denotes Moreover, Ro52/TRIM21 enhances IRF8-dependent inflammatory cytokine expression via K63-linked ubiquitination rather than degradation [9] .
T31 4940-5007 Sentence denotes Thus, Ro52/TRIM21 positively and negatively regulates various IRFs.
T32 5008-5221 Sentence denotes To escape from host innate immune responses, viruses have acquired mechanisms that antagonize or inhibit innate immune receptor-triggered type I IFN induction, as a result of co-evolution between host and viruses.
T33 5222-5445 Sentence denotes Zheng et al. sought to analyze evasion mechanisms of the mouse hepatitis virus A59 (MHV-A59), which belongs to coronaviruses, a family that also includes members such as severe acute respiratory syndrome (SARS) coronavirus.
T34 5446-5575 Sentence denotes They found that IRF3 is ubiquitinated, and this ubiquitination is required for its nuclear translocation rather than degradation.
T35 5576-5844 Sentence denotes They demonstrated that Papain-like protease domain 2 (PLP2) of nonstructural protein 3 (nsp3), which contains conserved deubiquitinase (DUB) motif, binds to IRF3 and causes its de-ubiquitination to prevent its nuclear localization, thereby suppressing IFNβ production.
T36 5845-6000 Sentence denotes Moreover, they provided evidence that IRF3 is modified by K48-and K63linked polyubiquitin chains, and PLP2 de-ubiqutinates both types via its DUB activity.
T37 6001-6103 Sentence denotes Thus, the DUB activity of PLP2 is responsible for coronavirus inhibition of host type I IFN induction.
T38 6104-6228 Sentence denotes A recently identified cellular DUB, DUBA, is capable of inhibiting TRAF3 activation, thus suppressing IRF3 activation [10] .
T39 6229-6362 Sentence denotes PLP2 may have a similar role to DUBA, although future study will be required to investigate whether PLP2 suppresses TRAF3 activation.
T40 6363-6483 Sentence denotes Taken together, these two studies suggest that IRF3 activation is positively and negatively regulated by ubuquitination.
T41 6484-6634 Sentence denotes Virus infection may trigger K48-and K63-linked ubiquitination of IRF3 in the cytoplasm, which is prerequisite for promoting its nuclear translocation.
T42 6635-6778 Sentence denotes In the nucleus, IRF3 ubiquitination (perhaps K48-linked) may be linked to degradation that is required for termination of type I IFN responses.
T43 6779-6850 Sentence denotes IRF3 plays a key role in virus infection-induced type I IFN production.
T44 6851-6941 Sentence denotes Thus, inhibition of IRF3 activation is an efficient way to terminate type I IFN responses.
T45 6942-7066 Sentence denotes In this respect, many viruses have acquired mechanisms that suppress IRF3 activation to escape from host type I IFN effects.
T46 7067-7222 Sentence denotes Thus, control of IRF3 activation via ubiquitination will be a target for designing therapeutic strategies against viral infection and autoimmune disorders.