HCMV-encoded US7 and US8 act as antagonists of innate immunity by distinctively targeting TLR-signaling pathways

Abstract

The mechanisms by which many human cytomegalovirus (HCMV)-encoded proteins help the virus to evade immune surveillance remain poorly understood. In particular, it is unknown whether HCMV proteins arrest Toll-like receptor (TLR) signaling pathways required for antiviral defense. Here, we report that US7 and US8 as key suppressors that bind both TLR3 and TLR4, facilitating their destabilization by distinct mechanisms. US7 exploits the ER-associated degradation components Derlin-1 and Sec61, promoting ubiquitination of TLR3 and TLR4. US8 not only disrupts the TLR3-UNC93B1 association but also targets TLR4 to the lysosome, resulting in rapid degradation of the TLR. Accordingly, a mutant HCMV lacking the US7-US16 region has an impaired ability to hinder TLR3 and TLR4 activation, and the impairment is reversed by the introduction of US7 or US8. Our findings reveal an inhibitory effect of HCMV on TLR signaling, which contributes to persistent avoidance of the host antiviral response to achieve viral latency.

Hypoxia-Inducible Ubiquitin Specific Peptidase 13 Contributes to Tumor Growth and Metastasis via Enhancing the Toll-Like Receptor 4/Myeloid Differentiation Primary Response Gene 88/Nuclear Factor-κB Pathway in Hepatocellular Carcinoma

“…Heat shock protein 27 (HSP27) has been identified as a regulator in facilitating endocytosis, ubiquitination, and degradation of TLR4 (Li et al, 2019). US7 and US8, which are encoded by human cytomegalovirus (HCMV), contribute to ubiquitination-mediated degradation of TLR3 and TLR4 (Park et al, 2019). Also, the ubiquitin E3 ligase Triad3A is previously demonstrated to promote TLR4 and TLR9 ubiquitination and degradation (Chuang and Ulevitch, 2004;Lu et al, 2020).…”

Human Cytomegalovirus-Encoded microRNAs Can Be Found in Saliva Samples from Renal Transplant Recipients

“…SNAP23 and CDC42 are components of the secretory pathway and may affect levels of circulating cytokines [ 17 ]. US7 promotes the degradation of toll-like receptors (TLR) 3 and 4 via ubiquitin-dependent pathways [ 23 ]. TLR3 detects dsRNA, which is generated by both RNA and DNA viruses.…”

Functional Profile of Human Cytomegalovirus Genes and Their Associated Diseases: A Review

“…The IE1 and IE2 proteins, which are synthesized after HCMV infection, can inhibit the IFN signal transduction and thereby inhibit the innate immune response (Paulus and Nevels, 2009). In addition, it has been suggested that US10 attenuates IFN-β (Park et al, 2019). The inhibition of cGAS activation and MITA trafficking by UL42 is contributes to the evasion of immune antiviral immunity by HCMV (Fu et al, 2019).…”