TRIM21

TRIM21 is the acronym for "Tripartite motif containing-21" a cytosolic ubiquitin ligase and an antibody receptor. TRIM 21 is a member of the TRIM protein family, which comprises>70 members with different functions. All TRIM proteins are characterized by the possession of three distinctive domains:

• an N-terminal RING finger
• one or two B-box domains and
• a coiled-coil.

TRIM21 exhibits antiviral functions. It provides a kind of last line of defense against invading viruses. Here, Trim 21 acts as a sensor that intercepts antibody-coated viruses that have escaped extracellular neutralization and have breached the cell membrane.

Upon binding of antibodies attached to viruses, TRIM21 triggers a coordinated effector and signaling response that prevents viral replication while simultaneously establishing an antiviral cellular state. This dual function is tightly regulated by auto-ubiquitination and phosphorylation. In addition, TRIM21 can act synergistically with the complement system.

Extracellular virus neutralization is thought to require specific antibody occupancy of certain epitopes to prevent entry into cells. However, viruses are known to have immunodominant epitopes that direct the polyclonal antibody response to non-entry neutralizing epitopes. This implies that some viruses and bacteria have the ability to invade the cell membrane and enter the cytosol even when opsonized with antibodies.

Such opportunistic pathogens are sensed by cytosolic TRIM21, which triggers a coordinated effector and signaling response that prevents viral replication. Antibody-opsonized non-enveloped viruses are rapidly recognized as targets and induce an innate immune response. Bacteria complexed by antibodies also trigger innate immune signaling with autophagy (Rakebrandt N et al. 2014).

In both pathogens, TRIM21 acts as a link between the intrinsic cellular self-defense system and adaptive immunity by using the diversity of the antibody repertoire to recognize invaders (Randow F et al. 2013). This distinguishes TRIM21 from other members of the TRIM protein family with antiviral functions, as these members usually recognize the invading pathogen directly (Bottermann M et al. 2018).

TRIM21 recognition also differs from that of other innate sensors, such as pattern-recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) (Odendall C et al. (2017). Instead, TRIM21 treats the shift of antibodies from the extracellular to the intracellular environment as a danger-associated molecular pattern (DAMP). Antiviral functions through TRIM21 may also parallel protective antiviral mechanisms mediated by the complement system (Tam JC et al. (2014) ).

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2. Bottermann M et al. (2019) Complement C4 prevents viral infection through capsid inactivation. Cell Host Microbe 25: 617-619

3. Foss S et al (2019) TRIM21-From Intracellular Immunity to Therapy. Front. Immunol doi.org/10.3389/fimmu.2019.02049

4. Odendall C et al. (2017) Activation and pathogenic manipulation of the sensors of the innate immune system. Microbes Infect. (2017) 19:229-37. doi: 10.1016/j.micinf.2017.01.003
5. Rakebrandt N et al (2014) Antibody- and TRIM21-dependent intracellular restriction of Salmonella enterica. Pathog Dis72:131-137.
6. Randow F et al. (2013) Cellular self-defense: how cell-autonomous immunity protects against pathogens. Science 340:701-706.
7. Tam JC et al. (2014) Intracellular sensing of complement C3 activates cell autonomous immunity. Science 345:1256070.