Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21
William A McEwan, Jerry C H Tam, Ruth E Watkinson, Susanna R Bidgood, Donna L Mallery & Leo C James. Nat Immunol. 2013 Apr;14(4):327-36

Speaker: Wei-Jheng Hunag (黃偉政)                Time: 15:00~16:00, Oct 16, 2013

Commentator: Dr. Jenn-Wei Chen (陳振暐 老師)     Place: Room 601

Abstract

The tripartite motif (TRIM) family of proteins comprises 70 members in the human genome, including TRIM21. TRIM proteins are involved in diverse cellular processes, including cell proliferation, differentiation, development, oncogenesis and apoptosis. Within the TRIM family, an expanding group of proteins, TRIM1, TRIM5α, TRIM19, TRIM22, and TRIM32, have been shown to target retroviruses and prevent their replication inside the cells (1). TRIM21 is a cytosolic antibody receptor and has been shown to mediate an intracellular antiviral immune response by binding and targeting virions for destruction in the proteasome. This process potently neutralizes viral infection and has been termed antibody-dependent intracellular neutralization (ADIN) (2). In this study, the authors found that recognition of intracellular antibodies by TRIM21 activates immune signaling through the synthesis of unanchored Lys63 (K63)-linked ubiquitin chains. In addition, they found that TRIM24 detects the incoming virus-antibody complexes and stimulates the transcription factor pathways of NF-kB, AP-1, and IRFs, resulting in the production ofproinflammatory cytokines and the induction of an antiviral state. Further, the authors provided evidence showing that Trim21 signaling from the antibody-TRIM21 detection system is independent of its neutralization activity, cell-surface FcRs and known PAMPs, but is dependent on TAK1, IKKα and IκB. Take together, this study demonstrated the existence of a pathogen detection mechanism that allows cells to stimulate broad-spectrum immunity after penetration of their cytosol by antibody-bound pathogens.

Reference

1.         Leo C. James, Anthony H. Keeble, Zahra Khan, David A. Rhodes, and John Trowsdale. Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function. Proc Natl Acad SciUSA. (2007) Apr 10;104(15):6200-5.

2.         Felix Hauler, Donna L. Mallery, William A. McEwan, Susanna R. Bidgood, and Leo C. James. AAA ATPase p97/VCP is essential for TRIM21-mediatedvirus neutralization. Proc Natl AcadSci USA. (2012) Nov 27;109(48):19733-8.