Ovarian tumor domain proteases in pathogen infection

• Published in: Trends in microbiology (Regular ed.) 2022-01, Vol.30 (1), p.22-33
• Main Authors: Schlüter, Dirk, Schulze-Niemand, Eric, Stein, Matthias, Naumann, Michael
• Format: Article
• Language: English
• Subjects: Humans; ISG15; multivalent recognition; NF-κB; Ovarian cancer; Ovarian Neoplasms; pathogen-encoded deubiquitinylases; Peptide Hydrolases - metabolism; pharmacological targets; Protein Binding; Tumors; ubiquitin; Ubiquitin - chemistry; Ubiquitin - metabolism
• ISSN: 0966-842X; 1878-4380
• DOI: 10.1016/j.tim.2021.04.002

With the aim of overcoming host immune responses, and to permit persistence, numerous bacterial and viral pathogens have evolved effective strategies to control the activity of ovarian tumor domain proteases (OTUs), a group of deubiquitinylases crucial for regulating ubiquitin-modified proteins. Due to the important role of eukaryotic OTUs in cellular physiology, it is not surprising that pathogens have evolutionarily developed effector proteins which mimic host OTUs. Here, we focus on recent findings that illustrate how pathogen-encoded OTUs modulate eukaryotic host proteins and how they are implicated in cellular dysregulation. Further, we discuss the biological effects of OTUs in the context of structural features and pharmacological targeting. We point out the potentiality of selective OTU inhibitors, which shield ubiquitin-binding sites, as pharmacologic targets to treat harmful infections. During pathogen infections, certain deubiquitinylases – ovarian tumor domain proteases (OTUs) – play an important role in the orchestration/induction of protective cellular host responses.Many pathogens have evolved effector proteins which mimic eukaryotic OTUs and converge on highly conserved cellular processes such as inflammation, DNA repair, and cell survival in order to manipulate the host cell to their advantage.The distinct structure and biological effects of viral OTUs make them attractive for pharmacologic targeting to treat harmful infections.Since therapeutic active-site inhibitors of OTUs will not be selective, an extension to larger and more hydrophobic small molecules – that also shield the ubiquitin-binding sites – appears promising.