Proteomics approaches for the identification of protease substrates during virus infection

Adv Virus Res. 2021;109:135-161. doi: 10.1016/bs.aivir.2021.03.003. Epub 2021 Apr 20.


Proteases precisely and irreversibly catalyze the hydrolysis of peptide bonds, regulating the fate, localization, and activity of many proteins. Consequently, proteolytic activity plays an important role in fundamental cellular processes such as differentiation and migration, immunological and inflammatory reactions, apoptosis and survival. During virus infection, host proteases are involved in several processes, from cell entry to initiation, progression and resolution of inflammation. On the other hand, many viruses encode their own highly specific proteases, responsible for the proteolytic processing of viral proteins, but, at the same time, to cleave host proteins to corrupt antiviral host responses and adjust protein activity to favor viral replication. Traditionally, protease substrate identification has been addressed by means of hypothesis-driven approaches, but recent advances in proteomics have made a toolkit available to uncover the extensive repertoire of host proteins cleaved during infection, either by viral or host proteases. Here, we review the currently available proteomics-based methods that can and have contributed to the systematic and unbiased identification of new protease substrates in the context of virus-host interactions. The role of specific proteases during the course of virus infections will also be highlighted.

Keywords: Degradomics; Immune evasion; N-terminomics; Polyprotein cleavage; Protein-protein interactions; Substrate discovery; Viral protease.

Publication types

  • Review

MeSH terms

  • Animals
  • Books
  • Host Microbial Interactions*
  • Humans
  • Mice
  • Peptide Hydrolases / metabolism*
  • Proteolysis
  • Proteomics / methods*
  • Viral Proteins / metabolism*
  • Virus Diseases / physiopathology*
  • Virus Replication


  • Viral Proteins
  • Peptide Hydrolases