UC San Diego

Many pathogens encode proteases that serve to antagonize the host immune system. In particular, viruses with a positive-sense single-stranded RNA genome ((+)ssRNA), including picornaviruses, flaviviruses, and coronaviruses, encode proteases that are not only required for processing the viral polyprotein into functional units but also manipulate crucial host cellular processes through their proteolytic activity. Because these proteases must coordinate both the cleavage of numerous polyprotein sites and subversion of host immunity, evolution of viral proteases is expected to be highly constrained. Despite this strong evolutionary constraint, these viral proteins and host immune factors are engaged in “evolutionary arms races” that results in diverse protease-host interactions even within closely related species. In some cases, rapid host gene evolution can result in avoidance of cleavage by viral proteases. In other, more recently described cases, hosts can evolve to bait viral proteases into cleaving them using a “tripwire” strategy of immune activation. Such data provide an explanation for why viral polyprotein sites evolve despite such a strong evolutionary constraint and highlight the importance of identifying and characterizing host proteins that are targeted by viral proteases. Moreover, such an evolutionary model provides insight into the changes in molecular functions between viral proteases and host factors, and underscores the role of viral proteases in viral host range, zoonosis and host immune gene evolution. Here, I describe a combined computational and functional approach that guide the discovery of new host targets of viral proteases, including the characterization of two new host innate immunity tripwires that trigger inflammation in response to viral protease activity.