Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21)

Abstract

Antibodies provide effective antiviral immunity despite the fact that viruses escape into cells when they infect. Here we show that antibodies remain attached to viruses after cell infection and mediate an intracellular immune response that disables virions in the cytosol. We have discovered that cells possess a cytosolic IgG receptor, tripartite motif-containing 21 (TRIM21), which binds to antibodies with a higher affinity than any other IgG receptor in the human body. TRIM21 rapidly recruits to incoming antibodybound virus and targets it to the proteasome via its E3 ubiquitin ligase activity. Proteasomal targeting leads to rapid degradation of virions in the cytosol before translation of virally encoded genes. Infection experiments demonstrate that at physiological antibody concentrations TRIM21 neutralizes viral infection. These results reveal an intracellular arm of adaptive immunity in which the protection mediated by antibodies does not end at the cell membrane but continues inside the cell to provide a last line of defense against infection. V iruses and their hosts have been coevolving for millions of years, and this has given rise to a complex system of immunity traditionally divided into innate and adaptive responses. Innate immunity comprises germ-line encoded receptors and effector mechanisms that recognize pathogen-associated molecular patterns (PAMPs) (1). The advantage of innate immunity is that it is fast and generic; however, viruses are adept at avoiding recognition by inhibiting innate immunity or by changing their molecular patterns. In contrast, adaptive immunity can clear a host of infection and provide protection against future infection. Unlike the PAMP receptors of innate immunity, adaptive immunity uses proteins such as antibodies to target pathogens. Antibodies are unique in the human body in that they evolve during the lifetime of an individual and can continue to target evolving pathogens (2). The weakness of adaptive immunity is that it can take 1 to 2 wk to reach full effectiveness. Moreover, the dogma of antibody immunity for the last 100 y has been that antibodies only provide extracellular protection (3). It is thought that once a virus has entered the cytosol of a cell, antibodies are helpless to prevent its infection.Recently we described an intracellular cytosolic protein called tripartite motif-containing 21 (TRIM21) that is capable of binding to an invariant region of antibody molecules via its PRYSPRY domain (4). We found this activity to be structurally, thermodynamically, and kinetically conserved across mammals (5). However, antibodies are extracellular proteins, as are all known mammalian IgG receptors (with the exception of FcRn, which is intracellular but not cytosolic). It therefore seemed incongruous to us that TRIM21 should be a universally conserved intracellular protein and yet be a high-affinity, highly specific IgG receptor. We hypothesized that there might be an antibody effector mechanism inside cells, mediated by TRIM21. Here we demonstrate the existence of...

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