key: cord-0925799-gz2845yy authors: Thomas, E.; Saad, Ramy title: Sequence homology between human PARP14 and the SARS-CoV-2 ADP ribose 1’-phosphatase date: 2020-06-11 journal: Immunol Lett DOI: 10.1016/j.imlet.2020.05.008 sha: 04765bc28a1523f6394bfc72b6c360b443291984 doc_id: 925799 cord_uid: gz2845yy • In support of the theory that coronaviral ADRP enzymes evolved to counteract the anti-viral immune signaling mediated by PARP14, we present sequence homology between the ADP-ribose-binding sites of the two proteins. • Interestingly this homology is even more pronounced in bat species. • We believe this model provides crucial information for the consideration of potential therapeutic interventions, based on the PARP axis in COVID-19. Thomas E. Webb -University College London Hospital, 235 Euston Rd, Bloomsbury, London NW1 2BU Ramy Saad -Royal Sussex County Hospital, Barry Building, Eastern Rd, Brighton BN2 5BE Highlights  In support of the theory that coronaviral ADRP enzymes evolved to counteract the anti-viral immune signaling mediated by PARP14, we present sequence homology between the ADPribose-binding sites of the two proteins.  Interestingly this homology is even more pronounced in bat species.  We believe this model provides crucial information for the consideration of potential therapeutic interventions, based on the PARP axis in COVID-19. 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 (2, 6) ( Figure 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). 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 ADPribose-binding strategy. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f PARP14 has been found to regulate STAT6-dependent transcription to promote the Th2 response and IL-4 release (5, 13) . 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 (Figure 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) 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 (19, 20) . 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