PUTTING A FACE ON A CLASS OF VIRAL DEUBIQUITINATING ENZYMES
March 12th, 2007
(l to r) Authors Wilhelm Weihofen, Rachelle Gaudet and Christian Schlieker
Herpesviruses (members of the Herpesviridae family) are widespread pathogens, causing disease in humans and animals. The family name stems from the Greek herpein ("to creep"), referring to the latent, re-occurring infections caused by herpesviruses. Although half of us are infected by herpes simplex virus alone, the lucky majority will never experience any symptoms.
During acute infection, viral pathogens commandeer host cells for their propagation. Accordingly, they have evolved to disable or subvert to their own advantage the cellular enzymatic machinery that could otherwise be deployed against them to mount antiviral immune response. For example, several laboratories including the Ploegh lab (Whitehead Institute at MIT and affiliated with MCB) have recently discovered that many viruses feature proteins that subvert the host’s ubiquitin system, which controls protein fate by means of mono- and poly-ubiquitination. While poly-ubiquitination is most commonly employed to target a protein for degradation by the proteasome, mono-ubiquitinated proteins are very often bound by proteins containing ubiquitin-binding domains to initiate cell signaling. Deubiquitination, on the other hand, can be used to revert both processes. Ubiquitination and deubiquitination are tightly controlled by a collection of target-specific host proteins.
In this study, members of the Gaudet and Ploegh labs teamed up and showed that some herpesvirus-encoded cysteine proteases are not as picky as cellular deubiquitinating enzymes, since they indiscriminately cleave most ubiquitin molecules attached to host proteins (C. Schlieker, W. Weihofen, E. Frijns, L. Kattenhorn, R. Gaudet and H. Ploegh. Structure of a herpesvirus-encoded cysteine protease reveals a new class of deubiquitinating enzymes. Mol. Cell 2007). To reveal how these enzymes recognize and cleave ubiquitin from proteins, the murine cytomegalovirus cysteine protease was crystallized in complex with a ubiquitin-based suicide inhibitor, and the structure of the complex was determined by x-ray crystallography. The structure of the protease features a unique fold and mode of ubiquitin recognition when compared to known cellular deubiquitinating enzymes. The observed differences and the fact that the deubiquitinating activity of this protein is essential for the virus to sustain a productive infection could lead to the development of drugs targeted against herpesviruses. Furthermore, because this enzyme is specific for ubiquitinated substrates while so unspecific for the nature of the substrate, it might become a useful lab tool as a "ubiquitin razor".