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Abstract
Viruses interact with the host ubiquitination system in a variety of ways. Viral proteins are often a substrate for ubiquitination, which leads to proteasomal degradation. Viruses also have functions to modify the cellular ubiquitination machinery. Recently, deubiquitinating protease (DUB) activity has been found in many viral proteins. In herpesviruses, the DUB domain is found within the large tegument protein, which is conserved in all members of the herpesvirus family. Although a limited number of viral and cellular targets have been identified to date, accumulating evidence shows that herpesviral DUBs may primarily target key cellular regulators of immune signaling pathways to promote viral replication. In this review, we summarize the recent findings on viral DUBs. In particular, we focus on the herpesviral DUBs and their targets, and discuss their potential roles in the regulation of immune signaling pathways.
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Figure 1.
Amino acid alignment of the conserved catalytic active site region of the DUB domains from human herpesviruses. Amino acids in the conserved region surrounding the active site cysteine residue in the DUBs of human herpesviruses are aligned. Black boxes indicate conserved residues, and grey boxes indicate similar residues. The cysteine, aspartic acid, and histidine residues in the catalytic triad are indicated by asterisks.
Figure 2.
The NF-κB and IRF3 signaling pathways and the targets of herpesvirus DUBs. In EBV latent infection, NF-κB is activated by viral LMP1. TRAF6 associates with LMP1 and is constitutively polyubiquitinated. Activation of NF-κB confers cell survival and inhibits the spontaneous induction of lytic replication. Once lytic replication is induced, BPLF1 deubiquitinates and inactivates TRAF6 to block NF-κB signaling, promoting efficient viral genome replication. RIG-I is a cytosolic RNA sensor that recognizes viral RNA. Ubiquitination of RIG-I promotes its association with MAVS, and ubiquitination of TRAF3 mediates recruitment of the TBK1/IKK∊ complex, leading to activation of IRF3. KSHV ORF64 and HSV-1 UL36 deubiquitinate RIG-I and TRAF3, respectively, thus inhibiting the RIG-mediated activation of IRF3 and type I IFN production.
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