Human TBK1 blocking peptide

The Us11 protein encoded by herpes simplex virus 1 (HSV-1) functions to impair autophagy; however, the molecular mechanisms of this inhibition remain to be fully established. Here, we report that the Us11 protein targets tripartite motif protein 23 (TRIM23), which is a key regulator of autophagy-mediated antiviral defense mediated by TANK-binding kinase 1 (TBK1). In virus-infected cells, the Us11 protein drastically reduces the formation of autophagosomes mediated by TRIM23 or TBK1. This autophagy-inhibitory effect is attributable to the binding of the Us11 protein to the ARF domain in TRIM23. Furthermore, such interaction spatially excludes TBK1 from the TRIM23 complex that also contains heat shock protein 90 (Hsp90). When stably expressed alone in host cells, the Us11 protein recapitulates the observed phenotypes seen in cells infected with the US11-expressing or wildtype virus. Consistent with this, expression of the Us11 protein promotes HSV-1 growth, while expression of TRIM23 restricts HSV-1 replication in the absence of US11. Together, these results suggest that disruption of the TRIM23-TBK1 complex by the Us11 protein inhibits autophagy-mediated restriction of HSV-1 infection. IMPORTANCE Autophagy is an evolutionarily conserved process that restricts certain intracellular pathogens, including HSV-1. Although HSV-1 is well known to inhibit autophagy, little is known about the precise molecular mechanisms of autophagy inhibition. We demonstrate that the Us11 protein of HSV-1 spatially disrupts the TRIM23-TBK1 complex, which subsequently suppresses autophagy and autophagy-mediated virus restriction. Thus, expression of the Us11 protein facilitates HSV-1 replication. These data unveil new insight into viral escape from autophagy-mediated host restriction mechanisms.

Germline mutations in the human SAMHD1 gene cause the development of Aicardi-Goutieres Syndrome (AGS), with a dominant feature being increased systemic type I interferon(IFN) production. Here we tested the state of type I IFN induction and response to, in SAMHD1 knockout (KO) human monocytic cells. SAMHD1 KO cells exhibited spontaneous transcription and translation of IFN-beta and subsequent interferon-stimulated genes (ISGs) as compared to parental wild-type cells. This elevation of IFN-beta. and ISGs was abrogated via inhibition of the TBK1-IRF3 pathway in the SAMHD1 KO cells. In agreement, we found that SAMHD1 KO cells present high levels of phosphorylated TBK1 when compared to control cells. Moreover, addition of blocking antibody against type I IFN also reversed elevation of ISGs. These experiments suggested that SAMHD1 KO cells are persistently autostimulating the TBK1-IRF3 pathway, leading to an enhanced production of type I IFN and subsequent selfinduction of ISGs.