Viral proteases are highly specific and recognize conserved cleavage site sequences of ~6-8 amino acids. Short stretches of homologous host-pathogen sequences (SSHHPS) can be found in the viral polyprotein within the viral protease cleavage sites. We hypothesized that these sequences corresponded to specific host protein targets since &gt;40 host proteins have been shown to be cleaved by Group IV viral proteases, and one Group VI viral protease. Using PHI-BLAST and the viral protease cleavage site sequences, we searched the human proteome for host targets and analyzed the hit results. While the polyprotein and host proteins related to the suppression of the innate immune responses may be the primary targets of these viral proteases, we identified other cleavable host proteins. These proteins appear to be related to the virus-induced phenotype suggesting that some of the symptoms associated with Group IV viruses may be extractable directly from the viral genome sequence. Here we identify sequences cleaved by the SARS-CoV-2 PLpro (papain-like protease) in vitro within human MYH7 and MYH6 (two cardiac myosins linked to several cardiomyopathies), FOXP3 (an X-linked Treg cell transcription factor), ErbB4 (HER4), and vitamin-K dependent plasma protein S (PROS1 is an anti-coagulation protein that prevents blood clots). Zinc inhibited the cleavage of these host sequences in vitro. Other patterns emerged from multi-species sequence alignments of the cleavage sites which may have implications for the selection of animal models and zoonosis. SSHHPS/nsP is an example of a sequence-specific post-translational silencing mechanism.

SARS-CoV-2 SSHHPS recognized by the papain-like protease

ACS Fall 2021

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