Intracellular antibody-mediated degradation is a neutralization mechanism for viruses that have entered cells. Antiviral immunity can still be produced after infection because the antibodies remain attached to the virus and mediate an immune response capable of disabling the pathogen.
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Intracellular antibody-mediated degradation is dependent on the intracellular antibody effector tripartite motif-containing 21 (TRIM21) that binds to the antibody. The discovery of this mechanism revealed an intracellular branch of adaptive immunity as a last line of defense against infection.
Mechanism of intracellular antibody-mediated degradation
The mechanism of intracellular antibody-mediated degradation occurs in five steps:
- An immunoglobulin G (IgG) antibody binds to a target antigen presented on the virus outside the cell.
- The antibody bound virus infects the host cell.
- The intracellular antibody effector, TRIM21, binds to the antibody in the cytosol.
- The complex is directed to the proteasome through the ubiquitin ligase activity of TRIM21.
- The proteasome destroys virions through proteolysis.
Intracellular antibody-mediated degradation is a non-cytotoxic mechanism contrasting with other immune responses such as T-cell killing. The mechanism produces the parallel disposal of the antibody as the virus is antibody bound, but little change is found to TRIM21 levels.
This indicates that TRIM21 is either not degraded by the proteasome, or only a fraction of total cellular TRIM21 is affected because of degradation coupled to IgG binding. Intracellular antibody-mediated degradation occurs before transcription of viral genes, which means that the cell can be relieved of infection.
Roles in immune signaling and autoimmunity
Immune response was previously thought of as an extracellular process conducted by professional immune cells. Intracellular antibody-mediated degradation has filled a gap in understanding and shown the important role of nonprofessional immune cells for disabling pathogens.
The discovery of TRIM21 antibody-mediated degradation means that other existing mechanisms of antibody neutralization must be reassessed.
It is presumed that neutralization is effector-independent, but some models where the conditions are suitable for TRIM21 activity need to be reexamined.
The discovery of TRIM21 may explain a paradox in antibody neutralization where the accepted model requires a critical number of antibodies to bind to each virion.
This is so all receptor binding sites are blocked, preventing the virus from infecting the cell.
Empirical data had previously found that a critical number of antibodies were not necessary for neutralization; a single antibody is now known to be sufficient for an effector-based response.
Limitations of intracellular antibody-mediated degradation
Intracellular antibody-mediated degradation was first reported in an adenovirus infection, but should apply equally to other non-enveloped viruses as well. Non-enveloped viruses with a DNA genome are also more likely to be affected because the destruction of the capsid causes exposure to cytosolic DNases that break down DNA.
Other pathogens are considered less susceptible to the mechanism. Enveloped viruses escape effector-dependent neutralization because of their mode of entry into cells. When entering by fusion of the viral and plasma membranes, virus-bound antibodies will be left outside the cell.
Entry through endocytosis and fusion with the endocytotic vesicle will also mean that antibodies are retained inside the vesicle even as the capsid is released.
Any damage to the endosome or openings in the endosomal compartment could still lead to effective TRIM21 neutralization.
Potential use of therapeutic antibodies in intracellular space
Intracellular antibody-mediated degradation may potentially be exploited for therapeutic purposes. TRIM21 appears to be expressed across cell types and theoretically, all antibodies that are able to penetrate the cytoplasm will bind with TRIM21.
Nonetheless, intracellular antibody-mediated degradation is probably dependent on currently unknown factors which need to be understood before the mechanism can be enhanced for treating various diseases.
The potential for targeting tumors through antibodies binding to intracellular antigens is promising with current research linking TRIM21 function to previous work on the development of intrabodies (i.e. intracellular antibodies).
Further Reading
De novo antibody protein sequencing reveals novel functional and neutralizing antibodies post-SARS-CoV-2 vaccination