Mitochondrial C11orf83 is a potent Antiviral Protein Independent of interferon production

Abstract

Mitochondria have a central position in innate immune response via the adaptor protein MAVS in mitochondrial outer membrane to limit viral replication by inducing interferon production. Here, we reported that C11orf83, a component of complex III of electronic transfer chain in mitochondrial inner membrane, was a potent antiviral protein independent of interferon production. C11orf83 expression significantly increased in response to viral infection, and endows cells with stronger capability of inhibiting viral replication. Deletion of C11orf83 permits viral replication easier and cells were more vulnerable to viral killing. These effects mainly were mediated by triggering OAS3-RNase L system. C11orf83 overexpression induced higher transcription of OAS3, and knockdown either OAS3 or RNase L impaired the antiviral capability of C11orf83. Interestingly, the signaling from C11orf83 to OAS3-RNase L was independent of interferon production. Thus, our findings suggested a new antiviral mechanism by bridging cell metabolic machinery component with antiviral effectors.

Functional and metabolic fitness of human CD4+ T lymphocytes during metabolic stress

“…These pathways were impaired by short-term inhibition of mitochondrial ATP production in memory CD4 + T cells and either inhibition of mitochondrial ATP or complex I in naive CD4 + T cells. Oligomycin interferes with OAS3 and RNASEL in innate immune cells (Wu et al, 2016;Yang et al, 2017; Data are represented as mean value. Comparisons to the control conditions of 5 mM glucose were made using repeated-measures one-way ANOVA with a single pooled variance and uncorrected Fishers' least significant difference.…”

“…These pathways were impaired by short-term inhibition of mitochondrial ATP production in memory CD4 + T cells and either inhibition of mitochondrial ATP or complex I in naive CD4 + T cells. Oligomycin interferes with OAS3 and RNASEL in innate immune cells ( Wu et al, 2016 ; Yang et al, 2017 ; Skrivergaard et al, 2019 ). Here, we show that oligomycin strongly down-regulated OAS1-3 and OASL and up-regulated RNASEL in activated T cells.…”

Mitochondrion‐located peptides and their pleiotropic physiological functions

“…Its expression was significantly increased in 293T cells after vesicular stomatitis virus (VSV) infection. Overexpression of UQCC3 in 293T cells inhibited virus replication while deletion of UQCC3 had the opposite effect [76]. UQCC3 regulated the expression of oligoadenylate synthetases which are the activators of RNase L, the terminator of virus replication.…”

Innate Antiviral Immunity in the Skin

“…Host antiviral proteins that have demonstrated antiviral actions within cells present temporarily or permanently present in the skin (see Glossary) and/or are active against skin-tropic viruses are listed in Table 1. One of these antiviral proteins is oligoadenylate synthetase s (OAS2), which identifies viruses through binding of viral dsRNA and activating latent RNase (RNase L), which subsequently leads to the degradation of viral RNA [12]. OAS proteins can also function through an RNase L-independent mechanism [13] Within the skin, antiviral proteins, such as OAS family members, myxovirus resistance proteins (MX) GTPases, and Interferon-stimulated gene 15 (ISG-15) are expressed in various cell types.…”

“…IRF-3 triggers the expression of antiviral IFIT1 and IFIT2 and to a smaller degree GBP1, OAS proteins, and ISG15 in T cells by binding to a region within their promoter gene homologous to their ISREs [11]. Furthermore, C11orf83, a component of complex III of the electron transport chain on the mitochondrial inner membrane, endows cells with a stronger capability to inhibit viral replication via the OAS3/RNAseL activity [12]. The IFN-independent pathways that produce antiviral proteins are of exceeding interest as they can offer insight into novel antiviral treatments, which would be a desired alternative to conventional antiviral therapies that have toxicity-associated side effects.…”