Tripartite motif-containing protein 21 also known as E3 ubiquitin-protein ligase TRIM21 is a protein that in humans is encoded by the TRIM21gene.[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.[3]
TRIM21 is an intracellular antibody effector in the intracellular antibody-mediated proteolysis pathway. It recognizes Fc domain[4] and binds to immunoglobulin G as well as 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.[3]
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.[5]
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.[6]
↑Monteith AJ, Kang S, Scott E, Hillman K, Rajfur Z, Jacobson K, Costello MJ, Vilen BJ (April 2016). "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. doi:10.1073/pnas.1513943113. PMID27035940.
↑Clift D, McEwan WA, Labzin LI, Konieczny V, Mogessie B, James LC, Schuh M (December 2017). "A Method for the Acute and Rapid Degradation of Endogenous Proteins". Cell. 171 (7): 1692–1706.e18. doi:10.1016/j.cell.2017.10.033. PMID29153837.
Further reading
Jones SK (June 1992). "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. doi:10.1111/j.1365-2133.1992.tb00098.x. PMID1610705.
Miyagawa S, Okada N, Inagaki Y, Kitano Y, Ueki H, Sakamoto K, Steinberg ML (March 1988). "SSA/Ro antigen expression in simian virus 40-transformed human keratinocytes". The Journal of Investigative Dermatology. 90 (3): 342–5. doi:10.1111/1523-1747.ep12456308. PMID2450143.
Tsugu H, Horowitz R, Gibson N, Frank MB (December 1994). "The location of a disease-associated polymorphism and genomic structure of the human 52-kDa Ro/SSA locus (SSA1)". Genomics. 24 (3): 541–8. doi:10.1006/geno.1994.1664. PMID7713506.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Igarashi T, Itoh Y, Fukunaga Y, Yamamoto M (1996). "Stress-induced cell surface expression and antigenic alteration of the Ro/SSA autoantigen". Autoimmunity. 22 (1): 33–42. doi:10.3109/08916939508995297. PMID8882420.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Bepler G, O'briant KC, Kim YC, Schreiber G, Pitterle DM (January 1999). "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. doi:10.1006/geno.1998.5659. PMID9933563.
Tseng CE, Miranda E, Di Donato F, Boutjdir M, Rashbaum W, Chan EK, Buyon JP (February 1999). "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. doi:10.1203/00006450-199902000-00018. PMID10022600.
Fabini G, Rutjes SA, Zimmermann C, Pruijn GJ, Steiner G (May 2000). "Analysis of the molecular composition of Ro ribonucleoprotein complexes. Identification of novel Y RNA-binding proteins". European Journal of Biochemistry. 267 (9): 2778–89. doi:10.1046/j.1432-1327.2000.01298.x. PMID10785401.
Kurien BT, Chambers TL, Thomas PY, Frank MB, Scofield RH (March 2001). "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. doi:10.1046/j.1365-3083.2001.00870.x. PMID11251884.
Di Donato F, Chan EK, Askanase AD, Miranda-Carus M, Buyon JP (September 2001). "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. doi:10.1016/S1357-2725(01)00055-3. PMID11461834.
Fukuda-Kamitani T, Kamitani T (July 2002). "Ubiquitination of Ro52 autoantigen". Biochemical and Biophysical Research Communications. 295 (4): 774–8. doi:10.1016/S0006-291X(02)00750-7. PMID12127959.
