Abstract
Tripartite motif-containing 21 (TRIM21) is a cytosolic immunoglobulin receptor that mediates antibody-dependent intracellular neutralization (ADIN). Here we show that TRIM21 potently inhibits the spreading infection of a replicating cytopathic virus and activates innate immunity. We used a quantitative PCR (qPCR)-based assay to measure in vitro replication of mouse adenovirus type 1 (MAV-1), a virus that causes dose-dependent hemorrhagic encephalitis in mice. Using this assay, we show that genetic ablation of TRIM21 or chemical inhibition of either the AAA ATPase p97/valosin-containing protein (VCP) or the proteasome results in a >1,000-fold increase in the relative level of infection in the presence of immune serum. Moreover, the TRIM21-mediated ability of antisera to block replication was a consistent feature of the humoral immune response in immunized mice. In the presence of immune sera and upon infection, TRIM21 also activates a proinflammatory response, resulting in secretion of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). These results demonstrate that TRIM21 provides a potent block to spreading infection and induces an antiviral state.
Highlights
Tripartite motif-containing 21 (TRIM21) is a cytosolic immunoglobulin receptor that mediates antibody-dependent intracellular neutralization (ADIN)
In order to determine whether genetic ablation of TRIM21 affects mouse adenovirus type 1 (MAV-1) infection and replication, we infected mouse embryonic fibroblast (MEF) cells derived from C57BL/6 wild-type (WT) and TRIM21Ϫ/Ϫ (K21)
We observed no differences between the WT and K21 MEF cells in viral titers (Fig. 1A), indicating that TRIM21 deletion has no significant impact on MAV-1 replication
Summary
Tripartite motif-containing 21 (TRIM21) is a cytosolic immunoglobulin receptor that mediates antibody-dependent intracellular neutralization (ADIN). We used a quantitative PCR (qPCR)-based assay to measure in vitro replication of mouse adenovirus type 1 (MAV-1), a virus that causes dose-dependent hemorrhagic encephalitis in mice Using this assay, we show that genetic ablation of TRIM21 or chemical inhibition of either the AAA ATPase p97/valosin-containing protein (VCP) or the proteasome results in a >1,000-fold increase in the relative level of infection in the presence of immune serum. MAV-1 is a nonenveloped icosahedral DNA virus [7], first isolated in 1960 [8], which causes dose-dependent hemorrhagic encephalitis in susceptible strains of mice [9] It is structurally [10] and genomically [11] similar to human adenovirus and provides an excellent model for the study of host and viral determinants of productive infection. Using MAV-1, we show that antibody-dependent TRIM21 activity provides a highly potent block to spreading viral infection
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