Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus

Zivcec, Marko; Scholte, Florine E. M.; Spiropoulou, Christina F.; Spengler, Jessica R.; Bergeron, Éric

Mammalian deubiquitinases are implicated as a negative feedback system of the IFN response [102] , and viral OTUs appear to perform similar functions. The CCHFV OTU domain is thought to suppress innate immune signaling by deconjugating Ub or ISG15. Conjugation of Ub (ubiquitination) and ISG15 (ISGylation) to lysine residues regulates IFN signaling, and targets several key components of the innate immune response, including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), RIG-I, MxA, interferon regulatory factor 3 (IRF3), signal transducer and activator of transcription 1 (STAT1), and protein kinase R (PKR) [103] [104] [105] [106] [107] [108] . The crystal structure of CCHFV OTU domain provided insights into Ub and ISG15 binding specificity and allowed the design of CCHFV mutants specifically lacking activity against Ub or ISG15 [93, 109, 110] . Overexpression of the CCHFV OTU domain results in reduced general cellular ubiquitination and ISGylation levels. In addition, CCHFV OTU overexpression reduces the RIG-I/mitochondrial antiviral-signaling protein (MAVS)-mediated IFN-response, likely because this overexpression blocks ubiquitination of RIG-I [92, 94] . The putative role of the OTU in infection remains paradoxical, as ubiquitination of RIG-I by tripartite motif-containing protein 25 (TRIM25) activates it, whereas ISGylation of RIG-I negatively regulates RIG-I activation by competing with ubiquitination sites [103, 111] . More studies are required to understand how deubiquitination of RIG-I by a viral OTU may facilitate viral replication, while simultaneous removal of ISG15 moieties from RIG-I may also result in increased antiviral responses.