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Title: Biodiversity impact of host interferon-stimulated-gene-product 15 on the coronavirus Papain-like protease deISGylase functions

Author
item DACZKOWSKI, COURTNEY - University Of Georgia
item DZIMIANSKI, JOHN - University Of Georgia
item MANK, NICK - University Of Georgia
item DAS, PHANI - Oak Ridge Institute For Science And Education (ORISE)
item Faaberg, Kay
item PEGAN, SCOTT - University Of Georgia

Submitted to: European Society for Veterinary Virology
Publication Type: Abstract Only
Publication Acceptance Date: 10/10/2016
Publication Date: 10/19/2016
Citation: Daczkowski, C.M., Dzimianski, J., Mank, N.J., Das, P.B., Faaberg, K.S., Pegan, S.D. 2016. Biodiversity impact of host interferon-stimulated-gene-product 15 on the coronavirus Papain-like protease deISGylase functions. 6th European Congress of Virology. Paper No. P1-23.

Interpretive Summary:

Technical Abstract: Coronaviruses are single-stranded, positive sense RNA viruses whose members have severe impact on human health and cause significant economic hardships. Some pertinent examples include severe acute and Middle East respiratory syndromes (SARS-CoV; MERS-CoV), porcine epidemic diarrhea virus (PEDV), and porcine deltacoronavirus (PD-CoV). Intriguingly, these viruses possess a Papain-like protease (PLpro) that is suggested to have the dual functions of facilitating replication through processing of the polypeptide and down regulation of the host immune system. For the latter, this protease appears to reverse post-translational modification of proteins ubiquitin (Ub) and Ub-like interferon stimulated gene product 15 (ISG15). Surprisingly, Ub has been found to be completely conserved among eukaryotes suggesting these proteases catalytic effectiveness would not vary from one species to another. However, ISG15 is highly divergent with sequence identities as low as 55% among mammals and even lower when a broader range of animals is compared. This may suggest that PLpros from certain coronaviruses may be more effective at cleaving certain species ISG15 conjugates, playing a role in defining these viruses' zoonotic potential. To gain insight into this possible phenomenon, the activity of PLpros from SARS-CoV, PEDV, PD-CoV, and MERS-CoV as well as others were assessed against Ub as well as ISG15 originating from an assortment of species. Excitingly, this revealed an array of different preferences among PLpros whose underpinnings were further clarified through ITC and the structural elucidation of SARS PLpro in complex with either a mouse, or human ISG15 domain. These structures and associated biophysical information not only revealed key interactions, or lack there of, that may drive a protease to prefer one specie's ISG15 over another, but also the marked difference in how PLpro accommodates ISG15 versus its other substrate ubiquitin.