LitCovid-sentences  

PubMed:32188728 JSONTXT 32 Projects

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Id Subject Object Predicate Lexical cue
T1 0-114 Sentence denotes Structure-Guided Mutagenesis Alters Deubiquitinating Activity and Attenuates Pathogenesis of a Murine Coronavirus.
T2 115-189 Sentence denotes Coronaviruses express a multifunctional papain-like protease, termed PLP2.
T3 190-364 Sentence denotes PLP2 acts as a protease that cleaves the viral replicase polyprotein, and a deubiquitinating (DUB) enzyme which removes ubiquitin moieties from ubiquitin-conjugated proteins.
T4 365-547 Sentence denotes Previous in vitro studies implicated PLP2 DUB activity as a negative regulator of the host interferon (IFN) response, but the role of DUB activity during virus infection was unknown.
T5 548-778 Sentence denotes Here, we used X-ray structure-guided mutagenesis and functional studies to identify amino acid substitutions within the ubiquitin-binding surface of PLP2 that reduced DUB activity without affecting polyprotein processing activity.
T6 779-967 Sentence denotes We engineered a DUB mutation (Asp1772 to Ala) into a murine coronavirus and evaluated the replication and pathogenesis of the DUB mutant virus (DUBmut) in cultured macrophages and in mice.
T7 968-1252 Sentence denotes We found that the DUBmut virus replicates similarly as the wild-type virus in cultured cells, but the DUBmut virus activates an IFN response at earlier times compared to the wild-type virus infection in macrophages, consistent with DUB activity negatively regulating the IFN response.
T8 1253-1564 Sentence denotes We compared the pathogenesis of the DUBmut virus to the wild-type virus and found that the DUBmut-infected mice had a statistically significant reduction (p<0.05) in viral titer in livers and spleens at day 5 post-infection, albeit both wild-type and DUBmut virus infections resulted in similar liver pathology.
T9 1565-2000 Sentence denotes Overall, this study demonstrates that structure-guided mutagenesis aids the identification of critical determinants of PLP2-ubiquitin complex, and that PLP2 DUB activity plays a role as an interferon antagonist in coronavirus pathogenesis.IMPORTANCE Coronaviruses employ a genetic economy by encoding multifunctional proteins that function in viral replication and also modify the host environment to disarm the innate immune response.
T10 2001-2264 Sentence denotes The coronavirus papain-like protease 2 (PLP2) domain possesses protease activity, which cleaves the viral replicase polyprotein, and also DUB activity (de-conjugating ubiquitin/ubiquitin-like molecules from modified substrates) using identical catalytic residues.
T11 2265-2439 Sentence denotes To separate the DUB activity from the protease activity, we employed a structure-guided mutagenesis approach and identified residues that are important for ubiquitin-binding.
T12 2440-2572 Sentence denotes We found that mutating the ubiquitin-binding residues results in a PLP2 that has reduced DUB activity but retains protease activity.
T13 2573-2788 Sentence denotes We engineered a recombinant murine coronavirus to express the DUB mutant and showed that the DUB mutant virus activated an earlier type I interferon response in macrophages and exhibited reduced replication in mice.
T14 2789-2908 Sentence denotes The results of this study demonstrate that PLP2/DUB is an interferon antagonist and a virulence trait of coronaviruses.