Abstract
Arenaviruses cause severe diseases in humans but establish asymptomatic, lifelong infections in rodent reservoirs. Persistently-infected rodents harbor high levels of defective interfering (DI) particles, which are thought to be important for establishing persistence and mitigating virus-induced cytopathic effect. Little is known about what drives the production of DI particles. We show that neither the PPXY late domain encoded within the lymphocytic choriomeningitis virus (LCMV) matrix protein nor a functional endosomal sorting complex transport (ESCRT) pathway is absolutely required for the generation of standard infectious virus particles. In contrast, DI particle release critically requires the PPXY late domain and is ESCRT-dependent. Additionally, the terminal tyrosine in the PPXY motif is reversibly phosphorylated and our findings indicate that this posttranslational modification may regulate DI particle formation. Thus we have uncovered a new role for the PPXY late domain and a possible mechanism for its regulation.
Highlights
Arenaviruses are a family of rodent-borne viruses with a worldwide distribution
Several families of enveloped RNA viruses, including the arenaviruses, encode short amino acid motifs, called late domains, to hijack host proteins in the endosomal sorting complex required for transport (ESCRT) to drive the release of virus particles from the host cell’s outer membrane
Several virus-like particles (VLPs)-based studies indicate that Z drives viral particle release by virtue of one or more encoded viral late domain(s) (P(S/T)AP, YXXL, and/or PPXY), which can recruit proteins from the cellular endosomal sorting complex required for transport (ESCRT) pathway [10,11,12]
Summary
Arenaviruses are a family of rodent-borne viruses with a worldwide distribution. Several arenaviruses, including Lassa virus and Junín virus, cause hemorrhagic fever syndromes whereas infection with the prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), can lead to aseptic meningitis in immunocompetent individuals, high lethality in immunocompromised individuals, or severe birth defects in the developing fetus [2,3]. Arenaviruses enter cells via receptor-mediated endocytosis [7], undergo genomic replication and transcription in the cytoplasm [6], and assemble and bud new particles at the plasma membrane [8]. The Z protein, which lines the luminal side of the viral membrane, is responsible for a number of critical functions in the virus life cycle, including driving the process of viral particle assembly and budding [9]. Z can form virus-like particles (VLPs) in the absence of other viral proteins and is thought to be both necessary and sufficient for driving the budding process [10,11]
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