Molecular mechanisms of protease precursor autoprocessing of RNA viruses: a comprehensive review

Many viruses express their proteins in the form of large polyproteins comprising structural and non-structural (e.g. enzymatic) units that are released from the precursor through ordered proteolysis. Proteolytic processing of polyproteins is an indispensable regulatory step for virus maturation and replication that is carried out by the virus-encoded and/or cellular proteases. The activity of a viral protease that is expressed as a part of a polyprotein is controlled in part by the self-cleavage (autoprocessing) from the precursor. The mechanism of protease precursor processing has been established at the molecular level for various RNA virus proteases, including human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Both viral protease precursors are processed via intra- (in cis) and intermolecular (in trans) cleavages at the N- and C-termini, respectively, yielding the mature enzyme. The remarkably similar activation mechanisms of HIV and SARS-CoV-2 PRs suggest that other viral proteases are activated similarly. In this review, we provide a detailed overview on the protease precursor autoprocessing mechanism of HIV-1 and SARS-CoV-2 proteases and compare those to the activation mechanism of non-viral proteases from their zymogens. Also, we review the activation mechanism of other ss(+)RNA viruses that utilize the polyprotein pathway for their replication. Based on such comparison, it appears that the protease activation mechanisms of most enveloped ss(+)RNA viruses from their precursors share many common features, although they do not correlate directly with the evolutionary relationships, the presence or absence of viral envelope or the catalytic mechanism of the viral protease.