Antiviral Activity of a Small Molecule Deubiquitinase Inhibitor Occurs via Induction of the Unfolded Protein Response
Jeffrey W. Perry, et al. (2012) PLoS Pathog. 8( 7): e1002783.

Speaker: Wei-Jheng Hunag (黃偉政)                Time: 13:10~14:00, May 29, 2013

Commentator: Dr. Yao Chang (張堯 老師)      　　 Place: Room 601

Abstract

Ubiquitin (Ub) is a small 76 amino acid protein that can be covalently linked to cellular proteins in a post-translational manner through a series of Ub-modifying enzymes. It plays a key role in a vast number of normal cellular processes including the removal of misfolded or abnormal proteins, the cellular stress response, the removal of unneeded proteins during cell differentiation, cell cycle regulation and the cellular immune response. Ub-conjugating and Ub-deconjugating processes are precisely and tightly regulated. Removal of Ub by deubiquitinases (DUBs) is a critical step to counterbalance Ub conjugation. Ubiquitin-specific proteases (USPs) are the largest and most diverse DUB family. In this paper, the authors used WP1130, a small molecule inhibitor of a subset of cellular DUBs, as a probe to investigate the functions of DUBs during norovirus infections. They found that WP1130 treatment significantly inhibited replication of norovirus and several other RNA viruses, including encephalomyocarditis virus, Sindbis virus, and La Crosse virus. By using a chemical proteomics approach, they identified that the cellular DUB USP14 is a target of WP1130 and is required for optimal norovirus infection. Mechanistic studies suggested that inhibition of USP14 by WP1130 result in inositol-requiring enzyme 1(IRE1) activation and hence the activation of the unfolded protein response (UPR). Taken together, this study provided evidence that induction of UPR through cellular DUB inhibitor blocks virus infections and suggested that cellular DUBs and UPR  may represent novel targets for antiviral therapy.

Reference

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