Targeting CTP Synthetase 1 to Restore Interferon Induction and Impede Nucleotide Synthesis in SARS-CoV-2 Infection

Rao, Yunjiang; Wang, T; Qin, Cheng‐Feng; Espinosa, Bianca; Q, Liu; Ekanayake, Arunika; Zhao, Jun; Savas, Ali Can; Zhang, S; Zarinfar, Mehrnaz; Y, Liu; Zhu, Weiliang; Graham, Nicholas; Jiang, Taijiao; Zhang, C; Feng, Pinghui

doi:10.1101/2021.02.05.429959

Cited by 15 publications

(18 citation statements)

References 60 publications

(80 reference statements)

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“…As with cancer cells, depleting CTP pools via CTPS inhibition enhances the efficacy of cytidine analogs in slowing the proliferation of HIV-infected cells ( 52 ). Furthermore, a recent study revealed that two SARS-CoV-2 proteins interact with and activate CTPS1 ( 53 ). Remarkably, in addition to providing CTP necessary for SARS-CoV-2 replication, activated CTPS1 also deamidates interferon regulatory factor 3, thus suppressing interferon production and inhibiting the innate immune response ( 53 ).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, a recent study revealed that two SARS-CoV-2 proteins interact with and activate CTPS1 ( 53 ). Remarkably, in addition to providing CTP necessary for SARS-CoV-2 replication, activated CTPS1 also deamidates interferon regulatory factor 3, thus suppressing interferon production and inhibiting the innate immune response ( 53 ). Small-molecule CTPS inhibitors restore the innate immune response and suppress SARS-CoV-2 replication ( 53 ).…”

Section: Discussionmentioning

confidence: 99%

“…Remarkably, in addition to providing CTP necessary for SARS-CoV-2 replication, activated CTPS1 also deamidates interferon regulatory factor 3, thus suppressing interferon production and inhibiting the innate immune response ( 53 ). Small-molecule CTPS inhibitors restore the innate immune response and suppress SARS-CoV-2 replication ( 53 ). However, whether these inhibitors are selective for CTPS1 is unclear.…”

Section: Discussionmentioning

confidence: 99%

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Structural basis for isoform-specific inhibition of human CTPS1

Lynch

DiMattia

Albanese

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Cytidine triphosphate synthase 1 (CTPS1) is necessary for an effective immune response, as revealed by severe immunodeficiency in CTPS1-deficient individuals [E. Martin et al.], [Nature] [510], [288–292] ([2014]). CTPS1 expression is up-regulated in activated lymphocytes to expand CTP pools [E. Martin et al.], [Nature] [510], [288–292] ([2014]), satisfying increased demand for nucleic acid and lipid synthesis [L. D. Fairbanks, M. Bofill, K. Ruckemann, H. A. Simmonds], [J. Biol. Chem. ] [270], [29682–29689] ([1995]). Demand for CTP in other tissues is met by the CTPS2 isoform and nucleoside salvage pathways [E. Martin et al.], [Nature] [510], [288–292] ([2014]). Selective inhibition of the proliferative CTPS1 isoform is therefore desirable in the treatment of immune disorders and lymphocyte cancers, but little is known about differences in regulation of the isoforms or mechanisms of known inhibitors. We show that CTP regulates both isoforms by binding in two sites that clash with substrates. CTPS1 is less sensitive to CTP feedback inhibition, consistent with its role in increasing CTP levels in proliferation. We also characterize recently reported small-molecule inhibitors, both CTPS1 selective and nonselective. Cryo-electron microscopy (cryo-EM) structures reveal these inhibitors mimic CTP binding in one inhibitory site, where a single amino acid substitution explains selectivity for CTPS1. The inhibitors bind to CTPS assembled into large-scale filaments, which for CTPS1 normally represents a hyperactive form of the enzyme [E. M. Lynch et al.], [Nat. Struct. Mol. Biol.] [24], [507–514] ([2017]). This highlights the utility of cryo-EM in drug discovery, particularly for cases in which targets form large multimeric assemblies not amenable to structure determination by other techniques. Both inhibitors also inhibit the proliferation of human primary T cells. The mechanisms of selective inhibition of CTPS1 lay the foundation for the design of immunosuppressive therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Structural basis for isoform-specific inhibition of human CTPS1

Lynch

DiMattia

Albanese

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…ORF8 also has an inhibitory effect on the interferon pathway (Li et al, 2020;Rao et al, 2021), and Blanco-Melo et al…”

Section: Ll Open Access Isciencementioning

confidence: 99%

ORF8 contributes to cytokine storm during SARS-CoV-2 infection by activating IL-17 pathway

et al. 2021

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Recently, COVID-19 caused by the novel coronavirus SARS-CoV-2 has brought great challenges to the world. More and more studies have shown that severe patients may suffer from cytokine storm syndrome; however, there are few studies on its pathogenesis. Here we demonstrated that SARS-CoV-2 coding protein open reading frame 8 (ORF8) acted as a contributing factor to cytokine storm during COVID-19 infection. ORF8 could activate IL-17 signaling pathway and promote the expression of pro-inflammatory factors. Moreover, we demonstrated that treatment of IL17RA antibody protected mice from ORF8-induced inflammation. Our findings are helpful to understand the pathogenesis of cytokine storm caused by SARS-CoV-2, and provide a potential target for the development of COVID-19 therapeutic drugs.

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“…SARS-CoV-2 propagation, infection, and viral titration were performed as previously described (54). All SARS-CoV-2 related experiments were performed in the biosafety level 3 (BSL-3) facility (USC).…”

Section: Sars-cov-2 Virus Replication and Progeny Productionmentioning

confidence: 99%

The Roles of APOBEC-mediated RNA Editing in SARS-CoV-2 Mutations, Replication and Fitness

Liu

Kim

Calabrese

et al. 2021

Preprint

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During COVID-19 pandemic, mutations of SARS-CoV-2 produce new strains that can be more virulent and evade vaccines. Viral RNA mutations can arise from misincorporation by RNA-polymerases and modification by host factors. Recent SARS-CoV-2 sequence analyses showed a strong bias toward C-to-U mutation, suggesting that host APOBEC cytosine deaminases with immune functions may cause the mutation. We report the experimental evidence demonstrating that APOBEC3A and APOBEC1 can efficiently edit SARS-CoV-2 RNA to produce C-to-U mutation at specific sites. However, APOBEC-editing does not inhibit the viral RNA accumulation in cells. Instead, APOBEC3A-editing of SARS-CoV-2 promotes viral replication/propagation, suggesting that SARS-CoV-2 utilizes the APOBEC-mediated mutations for fitness and evolution. Unlike the unpredictability of random mutations, this study has significant implications in predicting the potential mutations based on the UC/AC motifs and surrounding RNA structures, thus offering a basis for guiding future antiviral therapies and vaccines against the escape mutants.

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Targeting CTP Synthetase 1 to Restore Interferon Induction and Impede Nucleotide Synthesis in SARS-CoV-2 Infection

Cited by 15 publications

References 60 publications

Structural basis for isoform-specific inhibition of human CTPS1

Structural basis for isoform-specific inhibition of human CTPS1

ORF8 contributes to cytokine storm during SARS-CoV-2 infection by activating IL-17 pathway

The Roles of APOBEC-mediated RNA Editing in SARS-CoV-2 Mutations, Replication and Fitness

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