TRIM21 explained

Tripartite motif-containing protein 21, also known as E3 ubiquitin-protein ligase TRIM21, is a protein that in humans is encoded by the TRIM21 gene.^{[1] [2]} Alternatively spliced transcript variants for this gene have been described but the full-length nature of only one has been determined. It is expressed in most human tissues.

Structure

TRIM21 is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING finger domain, a B-box type 1 and a B-box type 2 zinc finger, and a coiled coil region.^[2]

Function

TRIM21 is an intracellular antibody effector in the intracellular antibody-mediated proteolysis pathway. It recognizes Fc domain^[3] and binds to immunoglobulin G, immunoglobulin A^[4] and immunoglobulin M on antibody marked non-enveloped virions which have infected the cell. Either by autoubiquitination or by ubiquitination of a cofactor, it is then responsible for directing the virions to the proteasome. TRIM21 itself is not degraded in the proteasome unlike both the viral capsid and the bound antibody.^[5]

TRIM21 is part of the RoSSA ribonucleoprotein, which includes a single polypeptide and one of four small RNA molecules. The RoSSA particle localizes to both the cytoplasm and the nucleus.^[2]

Clinical significance

RoSSA interacts with autoantigens in patients with Sjögren's syndrome and systemic lupus erythematosus.^[2] In addition, the inability for lupus-prone macrophages to degrade immune complexes in the lysosome results in the leakage of autoantibodies into the cytosol that can bind to TRIM21 and enhance NF-κB signaling.^[6]

TRIM21 can be used to knockout specific proteins with their corresponding antibodies, a method known as Trim-Away. In this assay, TRIM21 and antibodies are delivered into cells through electroporation, and the targeted protein is degraded within a few minutes.^[7]

References

Further reading

• Jones SK . Ultraviolet radiation (UVR) induces cell-surface Ro/SSA antigen expression by human keratinocytes in vitro: a possible mechanism for the UVR induction of cutaneous lupus lesions . The British Journal of Dermatology . 126 . 6 . 546–53 . June 1992 . 1610705 . 10.1111/j.1365-2133.1992.tb00098.x . 24542694 .
• Itoh K, Itoh Y, Frank MB . Protein heterogeneity in the human Ro/SSA ribonucleoproteins. The 52- and 60-kD Ro/SSA autoantigens are encoded by separate genes . The Journal of Clinical Investigation . 87 . 1 . 177–86 . January 1991 . 1985094 . 295020 . 10.1172/JCI114968 .
• Chan EK, Hamel JC, Buyon JP, Tan EM . Molecular definition and sequence motifs of the 52-kD component of human SS-A/Ro autoantigen . The Journal of Clinical Investigation . 87 . 1 . 68–76 . January 1991 . 1985112 . 294993 . 10.1172/JCI115003 .
• Miyagawa S, Okada N, Inagaki Y, Kitano Y, Ueki H, Sakamoto K, Steinberg ML . SSA/Ro antigen expression in simian virus 40-transformed human keratinocytes . The Journal of Investigative Dermatology . 90 . 3 . 342–5 . March 1988 . 2450143 . 10.1111/1523-1747.ep12456308 .
• Chan EK, Di Donato F, Hamel JC, Tseng CE, Buyon JP . 52-kD SS-A/Ro: genomic structure and identification of an alternatively spliced transcript encoding a novel leucine zipper-minus autoantigen expressed in fetal and adult heart . The Journal of Experimental Medicine . 182 . 4 . 983–92 . October 1995 . 7561701 . 2192297 . 10.1084/jem.182.4.983 .
• Tsugu H, Horowitz R, Gibson N, Frank MB . The location of a disease-associated polymorphism and genomic structure of the human 52-kDa Ro/SSA locus (SSA1) . Genomics . 24 . 3 . 541–8 . December 1994 . 7713506 . 10.1006/geno.1994.1664 .
• Frank MB, McCubbin VR, Heldermon C . Expression and DNA binding of the human 52 kDa Ro/SSA autoantigen . The Biochemical Journal . 305 . 2 . 359–62 . January 1995 . 7832745 . 1136368 . 10.1042/bj3050359.
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Keech CL, Gordon TP, McCluskey J . Structural differences between the human and mouse 52-kD Ro autoantigens associated with poorly conserved autoantibody activity across species . Clinical and Experimental Immunology . 104 . 2 . 255–63 . May 1996 . 8625517 . 2200432 . 10.1046/j.1365-2249.1996.16726.x .
• Igarashi T, Itoh Y, Fukunaga Y, Yamamoto M . Stress-induced cell surface expression and antigenic alteration of the Ro/SSA autoantigen . Autoimmunity . 22 . 1 . 33–42 . 1996 . 8882420 . 10.3109/08916939508995297 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Bepler G, O'briant KC, Kim YC, Schreiber G, Pitterle DM . A 1.4-Mb high-resolution physical map and contig of chromosome segment 11p15.5 and genes in the LOH11A metastasis suppressor region . Genomics . 55 . 2 . 164–75 . January 1999 . 9933563 . 10.1006/geno.1998.5659 .
• Tseng CE, Miranda E, Di Donato F, Boutjdir M, Rashbaum W, Chan EK, Buyon JP . mRNA and protein expression of SSA/Ro and SSB/La in human fetal cardiac myocytes cultured using a novel application of the Langendorff procedure . Pediatric Research . 45 . 2 . 260–9 . February 1999 . 10022600 . 10.1203/00006450-199902000-00018 . free .
• Fabini G, Rutjes SA, Zimmermann C, Pruijn GJ, Steiner G . Analysis of the molecular composition of Ro ribonucleoprotein complexes. Identification of novel Y RNA-binding proteins . European Journal of Biochemistry . 267 . 9 . 2778–89 . May 2000 . 10785401 . 10.1046/j.1432-1327.2000.01298.x . free .
• Kurien BT, Chambers TL, Thomas PY, Frank MB, Scofield RH . Autoantibody to the leucine zipper region of 52 kDa Ro/SSA binds native 60 kDa Ro/SSA: identification of a tertiary epitope with components from 60 kDa Ro/SSA and 52 kDa Ro/SSA . Scandinavian Journal of Immunology . 53 . 3 . 268–76 . March 2001 . 11251884 . 10.1046/j.1365-3083.2001.00870.x . 7923255 . free .
• Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A . The tripartite motif family identifies cell compartments . The EMBO Journal . 20 . 9 . 2140–51 . May 2001 . 11331580 . 125245 . 10.1093/emboj/20.9.2140 .
• Di Donato F, Chan EK, Askanase AD, Miranda-Carus M, Buyon JP . Interaction between 52 kDa SSA/Ro and deubiquitinating enzyme UnpEL: a clue to function . The International Journal of Biochemistry & Cell Biology . 33 . 9 . 924–34 . September 2001 . 11461834 . 10.1016/S1357-2725(01)00055-3 .
• Fukuda-Kamitani T, Kamitani T . Ubiquitination of Ro52 autoantigen . Biochemical and Biophysical Research Communications . 295 . 4 . 774–8 . July 2002 . 12127959 . 10.1016/S0006-291X(02)00750-7 .

Notes and References

1. Frank MB, Itoh K, Fujisaku A, Pontarotti P, Mattei MG, Neas BR . The mapping of the human 52-kD Ro/SSA autoantigen gene to human chromosome 11, and its polymorphisms . American Journal of Human Genetics . 52 . 1 . 183–91 . January 1993 . 8094596 . 1682114 .
2. Web site: Entrez Gene: TRIM21 tripartite motif-containing 21.
3. James LC, Keeble AH, Khan Z, Rhodes DA, Trowsdale J . Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function . Proceedings of the National Academy of Sciences of the United States of America . 104 . 15 . 6200–5 . April 2007 . 17400754 . 1851072 . 10.1073/pnas.0609174104 . 2007PNAS..104.6200J . free .
4. Bidgood. Susanna. Tam. Jerry. McEwan. William. Mallery. Donna. James. Leo. 2014. Translocalized IgA mediates neutralization and stimulates innate immunity inside infected cells. Proceedings of the National Academy of Sciences of the United States of America. 111. 37. 13463–8. 10.1073/pnas.1410980111. 4169910. 2014PNAS..11113463B. 25169018. free.
5. Mallery DL, McEwan WA, Bidgood SR, Towers GJ, Johnson CM, James LC . Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21) . Proceedings of the National Academy of Sciences of the United States of America . 107 . 46 . 19985–90 . November 2010 . 21045130 . 2993423 . 10.1073/pnas.1014074107 . 2010PNAS..10719985M . free .
6. Monteith AJ, Kang S, Scott E, Hillman K, Rajfur Z, Jacobson K, Costello MJ, Vilen BJ . Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus . Proceedings of the National Academy of Sciences of the United States of America . 113 . 15 . E2142–51 . April 2016 . 27035940 . 4839468 . 10.1073/pnas.1513943113 . 2016PNAS..113E2142M . free .
7. Clift D, McEwan WA, Labzin LI, Konieczny V, Mogessie B, James LC, Schuh M . A Method for the Acute and Rapid Degradation of Endogenous Proteins . Cell . 171 . 7 . 1692–1706.e18 . December 2017 . 29153837 . 5733393 . 10.1016/j.cell.2017.10.033 .