Abstract
Tripartite motif (TRIM) proteins belong to a large family with many roles in host biology, including restricting virus infection. Here, we found that TRIM2, which has been implicated in cases of Charcot–Marie–Tooth disease (CMTD) in humans, acts by blocking hemorrhagic fever New World arenavirus (NWA) entry into cells. We show that Trim2-knockout mice, as well as primary fibroblasts from a CMTD patient with mutations in TRIM2, are more highly infected by the NWAs Junín and Tacaribe virus than wild-type mice or cells are. Using mice with different Trim2 gene deletions and TRIM2 mutant constructs, we demonstrate that its antiviral activity is uniquely independent of the RING domain encoding ubiquitin ligase activity. Finally, we show that one member of the TRIM2 interactome, signal regulatory protein α (SIRPA), a known inhibitor of phagocytosis, also restricts NWA infection and conversely that TRIM2 limits phagocytosis of apoptotic cells. In addition to demonstrating a novel antiviral mechanism for TRIM proteins, these studies suggest that the NWA entry and phagocytosis pathways overlap.
Highlights
Arenaviruses are enveloped single-stranded RNA viruses whose entry is mediated by the viral glycoprotein (GP), generated by proteolytic processing of a precursor into the envelope proteins GP1, GP2, and stable signal peptide (SSP), a third subunit required for virus–cell fusion [1]
New World arenaviruses (NWAs) are rodent-transmitted viruses that cause high mortality when they evolve the ability to infect humans. These clade B pathogenic viruses are known to bind to transferrin receptor 1 and other receptors on the cell surface, the steps leading to their entry into the cell are not well determined
We show that a host factor identified in a previous small interfering RNA screen, tripartite motif 2 (TRIM2), limits NWA endocytosis into cells
Summary
Arenaviruses are enveloped single-stranded RNA viruses whose entry is mediated by the viral glycoprotein (GP), generated by proteolytic processing of a precursor into the envelope proteins GP1, GP2, and stable signal peptide (SSP), a third subunit required for virus–cell fusion [1]. The clade B New World arenaviruses (NWAs), including Junın and Machupo viruses—the causative agents of Argentine and Bolivian hemorrhagic fever, respectively—use human but not mouse (Mus) transferrin receptor 1 (TfR1) for cell entry [2], whereas the Old World arenaviruses (OWAs) Lassa virus and lymphocytic choriomeningitis virus (LCMV) use alpha-dystroglycan [3]. Other clade B NWAs, such as Tacaribe virus, use TfR1s from their own host but not the human receptor (reviewed in [7]). It is generally accepted that OWAs enter cells via a macropinocytosis-like process that is clathrinand dynamin-independent, whether this is the case for NWAs is less clear [7, 14, 15]
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