Human Herpesvirus 6B U26 Inhibits the Activation of the RLR/MAVS Signaling Pathway

Abstract

U26 is one of the roseolovirus unique genes with unknown function. Human herpesvirus 6B (HHV-6B) pU26 is predicted to be an 8-transmembrane protein containing a mitochondrion location signal. Here, we analyzed U26 function during HHV-6B infection and find that (i) HHV-6B U26 is expressed at a very early stage during HHV-6B infection, and knockdown of it results in a significant decrease of HHV-6B progeny virus production; (ii) U26 inhibits the activation of the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR)/mitochondrial antiviral signaling protein (MAVS) signaling pathway, an important anti-HHV-6B infection innate immune response, by targeting MAVS protein for degradation; and (iii) a portion of U26 locates to the mitochondria, which could affect the mitochondrial membrane potential and finally leads to MAVS degradation. These findings indicate that HHV-6B U26 is a novel antagonistic viral factor against host innate antiviral immunity. IMPORTANCE HHV-6B (human herpesvirus 6B) is well known to evade host antiviral responses and establish a lifelong latent infection. How HHV-6B evades RNA recognition is still poorly understood. Our results indicate that HHV-6 U26 plays a vital role in RLR/MAVS signaling pathway activity. Knockout of endogenous MAVS could facilitate HHV-6B replication. The findings in this study could provide new insights into host-virus interactions and help develop a new therapy against HHV-6B infection.

Structural Models for Roseolovirus U20 And U21: Non-Classical MHC-I Like Proteins From HHV-6A, HHV-6B, and HHV-7

“…U20-U26 comprise a gene cluster specific to the Roseolovirus genus, sandwiched between clusters of genes shared within the betaherpesvirus subfamily or by the entire herpesvirus family ( Figure 6A ) ( 52 , 65 ). Generally, these genes are dispensable for viral growth ( 66 ) and involved in immune evasion: in addition to U20 and U21 described above, U24 has been implicated in endocytic recycling and protein degradation ( 67 – 69 ) and U26 has been shown to inhibit the RLR/MAVS signaling pathway ( 70 ). U20, U21, U23, and U24 are single-pass type I membrane glycoproteins, U25 is a soluble tegument protein, and U26 is a polytopic 8-pass integral membrane protein.…”

Activation and Evasion of RLR Signaling by DNA Virus Infection

“…For example, EBV can promote RIG-I degradation through the proteasomal pathway by recruiting an E3 ubiquitin ligase, the carboxyl-terminus of Hsp70 interacting protein (CHIP) to the RIG-I through EBV-encoded LMP1 (Chongfeng et al, 2018). Our previous studies found that human herpesvirus 6 (HHV-6), a DNA virus, can regulate the RLR/MAVS signaling pathway by affecting the mitochondrial membrane potential (Jiang et al, 2021). Here, we summarize the strategies that DNA viruses employed to evade the RLRs-mediated innate antiviral responses.…”

“…Many viruses encode viral proteases that directly cleave RLR, as mentioned above of EBV infection (Baglio et al, 2016). Since MAVS is critical for both RIG-I-and MDA5mediated signaling, many viral products, such as HCMV US9 and HHV-6 U26 proteins, target and cleave MAVS by inducing the leakage of mitochondrial MAVS for degradation (Choi et al, 2018;Jiang et al, 2021). Moreover, during HCMV infection RIG-I was significantly degraded (Scott, 2009).…”

“…RLRs recognize RNA virus genomes and/or their products, which plays an important role in initiating the antiviral innate immune response against various RNA viruses (Yoneyama et al, 2004;Rehwinkel and Gack, 2020). Interestingly, activation and downstream signal transduction of RLRs have also been recently observed during several DNA viruses' infections (Andrejeva et al, 2004;Gack et al, 2009;Ban et al, 2018;Koliopoulos et al, 2018;Zhang et al, 2020;Jiang et al, 2021).…”

Characterization of the HHV-6 U20 immunoevasin

“…U24 from HHV-6A, 6B and 7 is a tail-anchored protein whose expression results in reduced surface expression of T cell receptors (19, 20). U26 from HHV-6B inhibits innate antiviral responses by interfering with MAVS signaling (22). Surprisingly, although U20 from HHV-6A and -6B share 92% identity (Figure 1), recent studies ascribe different functions to HHV6A U20 and HHV6B U20.…”