Date Published: October 27, 2015
Publisher: Public Library of Science
Author(s): Ruth E. Watkinson, William A. McEwan, Jerry C. H. Tam, Marina Vaysburd, Leo C. James, Christopher F. Basler.
Encapsidation is a strategy almost universally employed by viruses to protect their genomes from degradation and from innate immune sensors. We show that TRIM21, which targets antibody-opsonized virions for proteasomal destruction, circumvents this protection, enabling the rapid detection and degradation of viral genomes before their replication. TRIM21 triggers an initial wave of cytokine transcription that is antibody, rather than pathogen, driven. This early response is augmented by a second transcriptional program, determined by the nature of the infecting virus. In this second response, TRIM21-induced exposure of the viral genome promotes sensing of DNA and RNA viruses by cGAS and RIG-I. This mechanism allows early detection of an infection event and drives an inflammatory response in mice within hours of viral challenge.
TRIM21 is a ubiquitously expressed high-affinity cytosolic antibody receptor and E3 ubiquitin ligase . TRIM21 intercepts incoming antibody-opsonized virions during cellular infection, mediating efficient post-entry neutralization  and innate immune signaling [3,4]. Unlike Fc gamma receptors, which phagocytose immune complexes, TRIM21 detects antibody-bound virions that enter the cytosol after attachment of the virus to its specific cellular receptor, endocytosis, and endosomal escape. TRIM21 therefore detects viruses during what could otherwise be a productive infectious event and protects cells of diverse tissue types . TRIM21 activation does not require any pathogen associated molecular pattern (PAMPs) or pattern recognition receptors (PRRs) but is based solely on sensing antibodies in the cytosol, an environment from which they are normally excluded. Consequently, TRIM21 is activated during infection by diverse pathogens including non-enveloped viruses and intracellular bacteria . TRIM21 participates in both naïve infection (through its ability to bind IgM) and secondary infection (by binding IgG). Upon in vivo challenge with mouse adenovirus 1 (MAV-1), mice lacking TRIM21 succumb to fatal viral infection within 7 days .
The early detection of infection is advantageous to the host. However, most viruses are shielded by a protein capsid that protects their genomes and associated PAMPs from immune sensing. As a consequence, incoming viral genomes are not always detected by pattern recognition receptors and detection often requires progeny genomes produced at later stages of the infectious cycle . For instance, the capsid of HIV-1 mediates a series of post-entry events that allows the virus to evade detection in macrophages by the cytosolic PRR cGAS[31,32]. Similarly, adenovirus infection proceeds via an elegant and highly coordinated stepwise process of disassembly, that may function in part to minimize exposure of the genome to DNA sensors in the cytoplasm. Here we show that TRIM21, which mediates the rapid degradation of incoming viral capsids in the cytosol, promotes the ability of sensors cGAS and RIG-I to detect the genomes of infectious viruses.