Sequence homology between human PARP14 and the SARS-CoV-2 ADP ribose 1’-phosphatase

Thomas Webb

Ramy Saad

Highlights

• There is amino acid sequence homology between the ADP-ribose binding sites of human PARP14 and SARS-CoV-2 ADRP.
• This homology is even more pronounced in bat species.
• The model proposed highlights the potential of the PARP axis to yield druggable targets for the treatment of COVID-19.

Thomas E. Webb: ten.shn@4bbew.samoht

^{Corresponding author.}ten.shn@4bbew.samoht

^{Both the authors are co-first authors.}

Received 2020 May 10; Accepted 2020 May 25.

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

The 16-subunit SARS-CoV-2 replicase-transcriptase complex is currently under intense investigation as a putative drug target.

In addition to containing proteinases, RNA-processing enzymes, and exonucleases, this complex exhibits ADP-ribose-1′-phosphatase (ADRP) activity [¹].

It is understood such activity may have emerged to counteract ADP-ribose-mediated signaling, which has been demonstrated to be vital in coordinating the mammalian immune response to viral infections [²].

Poly(ADP-ribose) polymerase family member 14 (PARP14) has numerous immunomodulatory roles including promotion of interferon expression in response to Coronaviridae infections [³], suppression of macrophage activation [⁴], and induction of the Th2 response [⁵].

We have found that the ADP-ribose-binding domains of both proteins share a significant degree of homology [²6] (Fig. 1 .). This supports a hypothesis that Coronaviridae ADRP enzymes may have co-evolved to counter the ADP-ribosylation activity of regulatory proteins such as PARP14 as they both bind ADP-ribose in the same context [⁶].

Fig. 1

32 % homology between the ADP-ribose-binding domain of SARS-CoV-2 and human PARP14*.

Within the class Mammalia, the ADP-ribose-binding domains of PARP isoforms from bat (Myotis) species are among the most similar to SARS-CoV-2 sequences (data not shown). This is consistent with the prevalent theory that the virus evolved from a strain found in bat species [⁷], with the inference being that co-evolution of the virus and the bat caused them to adopt the same ADP-ribose-binding strategy.

In mouse models, attenuation of the SARS-CoV ADRP increased the sensitivity of the virus to interferon α [⁸] and PARP14 inhibition caused a reduction in interferon β mRNA levels by an ADP-ribosylation-dependent mechanism [³]. Interferon γ can also increase the propensity for ADP-ribosylation of PARP14 [⁹]. The SARS-CoV ORF6 protein has been implicated in blockade of the transit of STAT1 into the nucleus, circumventing the interferon-α/β-mediated antiviral immune response [¹⁰]. It follows that the interferon axis and PARP14 activity appear conspicuously linked and recent literature has elucidated a role for interferon therapy in COVID-19 [¹¹].

Macrophage Activation Syndrome (MAS) has been found to complicate severe COVID-19 [¹²]. ADP-ribosylation of STAT1 by PARP14 suppresses macrophage activation, in opposition to PARP9 [⁴]. It is possible that viral suppression of STAT1 transit and ADP-ribose cleavage both contribute to MAS (Fig. 2 .).

Fig. 2

Graphical summary of the immune sequelae of the antagonism between the activity of human PARP14 and coronaviral ADRP.

PARP14 has been found to regulate STAT6-dependent transcription to promote the Th2 response and IL-4 release [⁵13]. This is particularly pronounced in lung tissue [¹⁴]. This has important ramifications for the host response to SARS-CoV-2 infection.

The Th2 response, which involves IL-4, IL-5 and IL-9 (Fig. 2.), serves to promote IgE release and encourage T-cell migration to inflamed tissue in allergic disease [¹⁵]. Of interest, Th2 predominance is noted in patients with atopic asthma [¹⁵], who appear underrepresented in severe COVID-19 cases [¹⁶] and one recent study revealed patients on anti-IL-4 therapy were found to exhibit no increased risk of severe COVID-19 [¹⁷].

In Middle East Respiratory Syndrome (MERS), a condition caused by the coronavirus EMC/2012, downregulation of Th2 cells and overexpression of innate system cytokines IL-1B and IL-6 contributes to the development of Acute Respiratory Distress Syndrome (ARDS) [¹⁸].

Similarly, in COVID-19, cytokines associated with the Th1 response (IL-1B, IL-6 and IL-8) correlate with morbidity and mortality [¹⁹]. Cytokine storm in COVID-19 is a pathogenic mechanism for morbidity and mortality, which again implicates dysregulation in the Th1 response [¹⁹20].

The effect of this proposed antagonism between SARS-CoV-2 ADRP and PARP14 activity appears to have myriad effects. These include skewing of the Th1:Th2 cytokine ratios, the evasion of host interferons, and macrophage activation. Susceptibility to MAS and cytokine storm, understood as poor prognostic factors in COVID-19, may be consequences of this relationship, compounded by a faltering host interferon response.

This might provide a model by which SARS-CoV-2 can maintain high levels of viral RNA, whilst simultaneously contributing to the deleterious effects to the host. Further experimental studies are needed to establish whether therapies within the PARP axis could be beneficial in severe COVID-19.

References

1. Saikatendu K.S., Joseph J.S., Subramanian V., Clayton T., Griffith M., Moy KStructural basis of severe acute respiratory syndrome coronavirus ADP-ribose-1’’-phosphate dephosphorylation by a conserved domain of nsP3. Structure. 2005;13(11):1665–1675.[Google Scholar]
2. Daugherty M.D., Young J.M., Kerns J.A., Malik H.SRapid evolution of PARP genes suggests a broad role for ADP-ribosylation in host-virus conflicts. PLoS Genet. 2014;10(5)[Google Scholar]
3. Grunewald M.E., Chen Y., Kuny C., Maejima T., Lease R., Ferraris DThe coronavirus macrodomain is required to prevent PARP-mediated inhibition of virus replication and enhancement of IFN expression. PLoS Pathog. 2019;15(5)[Google Scholar]
4. Iwata H., Goettsch C., Sharma A., Ricchiuto P., Goh W.W., Halu APARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation. Nat. Commun. 2016;7:12849.[Google Scholar]
5. Riley J.P., Kulkarni A., Mehrotra P., Koh B., Perumal N.B., Kaplan M.HPARP-14 binds specific DNA sequences to promote Th2 cell gene expression. PLoS One. 2013;8(12)[Google Scholar]
6. Egloff M.P., Malet H., Putics A., Heinonen M., Dutartre H., Frangeul AStructural and functional basis for ADP-ribose and poly(ADP-ribose) binding by viral macro domains. J. Virol. 2006;80(17):8493–8502.[Google Scholar]
7. Zhou P., Yang X.L., Wang X.G., Hu B., Zhang L., Zhang WA pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–273.[Google Scholar]
8. Kuri T., Eriksson K.K., Putics A., Zust R., Snijder E.J., Davidson A.DThe ADP-ribose-1’’-monophosphatase domains of severe acute respiratory syndrome coronavirus and human coronavirus 229E mediate resistance to antiviral interferon responses. J. Gen. Virol. 2011;92(Pt 8):1899–1905.[PubMed][Google Scholar]
9. Higashi H., Maejima T., Lee L.H., Yamazaki Y., Hottiger M.O., Singh S.AA Study into the ADP-Ribosylome of IFN-gamma-Stimulated THP-1 Human Macrophage-like Cells Identifies ARTD8/PARP14 and ARTD9/PARP9 ADP-Ribosylation. J. Proteome Res. 2019;18(4):1607–1622.[Google Scholar]
10. Frieman M., Yount B., Heise M., Kopecky-Bromberg S.A., Palese P., Baric R.SSevere acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane. J. Virol. 2007;81(18):9812–9824.[Google Scholar]
11. Sallard E., Lescure F.X., Yazdanpanah Y., Mentre F., Peiffer-Smadja NType 1 interferons as a potential treatment against COVID-19. Antiviral Res. 2020;178[Google Scholar]
12. McGonagle D., Sharif K., O’Regan A., Bridgewood CThe role of cytokines including Interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun. Rev. 2020[Google Scholar]
13. Mehrotra P., Riley J.P., Patel R., Li F., Voss L., Goenka SPARP-14 functions as a transcriptional switch for Stat6-dependent gene activation. J. Biol. Chem. 2011;286(3):1767–1776.[Google Scholar]
14. Mehrotra P., Hollenbeck A., Riley J.P., Li F., Patel R.J., Akhtar NPoly (ADP-ribose) polymerase 14 and its enzyme activity regulates T(H)2 differentiation and allergic airway disease. J. Allergy Clin. Immunol. 2013;131(2):521–531. e1-12. [Google Scholar]
15. Akdis C.A., Arkwright P.D., Bruggen M.C., Busse W., Gadina M., Guttman-Yassky EType 2 immunity in the skin and lungs. Allergy. 2020[PubMed][Google Scholar]
16. Halpin D.M.G., Faner R., Sibila O., Badia J.R., Agusti ADo chronic respiratory diseases or their treatment affect the risk of SARS-CoV-2 infection? Lancet Respir. Med. 2020[Google Scholar]
17. Carugno A., Raponi F., Locatelli A.G., Vezzoli P., Gambini D.M., Di Mercurio MNo evidence of increased risk for COVID-19 infection in patients treated with Dupilumab for atopic dermatitis in a high-epidemic area - Bergamo, Lombardy, Italy. J Eur Acad Dermatol Venereol. 2020[Google Scholar]
18. Alosaimi B., Hamed M.E., Naeem A., Alsharef A.A., AlQahtani S.Y., AlDosari K.MMERS-CoV infection is associated with downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated inflammatory innate immune response in the lower respiratory tract. Cytokine. 2020;126:154895.[Google Scholar]
19. Conti P., Ronconi G., Caraffa A., Gallenga C., Ross R., Frydas IInduction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J. Biol. Regul. Homeost. Agents. 2020;34(2)[PubMed][Google Scholar]
20. Ye Q., Wang B., Mao JCytokine storm in COVID-19 and treatment. J. Infect. 2020[PubMed][Google Scholar]