Alternative titles; symbols
HGNC Approved Gene Symbol: TRIM21
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38): 11:4,384,897-4,393,702 (from NCBI)
TRIM21 is an E3 ubiquitin ligase that controls responses to TLR2 agonists (Sjostrand et al., 2019).
Ro/SSA is a ribonucleoprotein particle composed of a single polypeptide and 1 of 4 small RNA molecules. Autoantibodies to Ro/SSA are present in 30 to 50% of patients with systemic lupus erythematosus (SLE; 152700) and in at least half of patients with primary Sjogren syndrome (270150). At least 2 distinct Ro/SSA polypeptides exist, a 60-kD form (TROVE2; 600063) and a 52-kD form. Using serum from a lupus patient to screen a human thymocyte cDNA expression library, Itoh et al. (1991) cloned TRIM21, which encodes the 52-kD Ro/SSA antigen. The deduced 475-amino acid protein has a calculated molecular mass of 54.1 kD. It has multiple N-terminal zinc finger motifs, a central leucine zipper, and a potential N-glycosylation site. Predicted hydrophobic regions are located at the N terminus, in the center of the molecule, and at the C terminus. Western blot analysis of lymphocyte extracts using patient serum confirmed that TRIM21 had an apparent molecular mass of 52 kD.
James et al. (2007) stated that the human TRIM21 protein contains an N-terminal RING finger that has E3 ligase activity, followed by a B box, 2 coiled-coil regions, and a long C-terminal PRYSPRY domain that binds IgG (see 147100) Fc fragments.
Using an EGFP reporter inserted into the Trim21 locus, Sjostrand et al. (2019) showed that Trim21 was expressed in macrophages and dendritic cells of mice.
Frank (1999) found that human RO52 expressed in insect cells bound double-stranded but not single-stranded DNA, and that zinc was required for binding. Sequencing oligonucleotides bound by RO52 revealed a purine-rich consensus motif, ARGRGGG(G/C)(A/C)GRNGA, in which R represents a purine and N indicates no consensus.
Using microarray analysis, Sjostrand et al. (2019) showed that maturation of bone marrow-derived macrophages (BMDMs) from Trim21 -/- mice was reduced in response to macrophage colony-stimulating factor (MCSF, or CSF2; 120420). Trim21 -/- BMDMs became hyporesponsive to stimulation with the TLR2 ligand PAM3CSK4, indicating that Trim21 was necessary for optimal responses to TLR2 agonists. Trim21 -/- BMDMs also became hyporesponsive to stimulation with Mycobacterium bovis Bacillus Calmette-Guerin (BCG), suggesting that Trim21 was also necessary for full responses to more complex stimuli.
Park et al. (2020) reported that the transfer of human bronchial epithelial cells from stiff to soft substrates caused a downregulation of glycolysis via proteasomal degradation of the rate-limiting metabolic enzyme phosphofructokinase (PFK; see PFKP, 171840). PFK degradation was triggered by the disassembly of stress fibers, which released the PFK-targeting E3 ubiquitin ligase TRIM21. Transformed non-small-cell lung cancer cells, which maintain high glycolytic rates regardless of changing environmental mechanics, retained PFK expression by downregulating TRIM21, and by sequestering residual TRIM21 on a stress fiber subset that is insensitive to substrate stiffness. Park et al. (2020) concluded that their data revealed a mechanism by which glycolysis responds to architectural features of the actomyosin cytoskeleton, thus coupling cell metabolism to the mechanical properties of the surrounding tissue. These processes enable normal cells to tune energy production in variable microenvironments, whereas the resistance of the cytoskeleton in response to mechanical cues enables the persistence of high glycolytic rates in cancer cells despite constant alterations of the tumor tissue.
James et al. (2007) solved the crystal structure of the TRIM21 PRYSPRY domain in complex with Fc to 2.35-angstrom resolution. The PRYSPRY binding surface was formed by 6 extended loops, and mutation analysis showed that asp355, trp381, trp383, and phe450 were required for Fc binding. PRYSPRY bound the CH2-CH3 site of Fc, and the stoichiometry was 2 molecules of PRYSPRY to 1 Fc fragment. Binding between PRYSPRY and Fc was independent of pH from pH 8 to pH 5, but it was highly salt sensitive. James et al. (2007) hypothesized that during autoimmune disease, anti-TRIM21 antibodies bind epitopes in the RING and B-box domains of TRIM21 via their antigen-binding fragment (Fab) and also bind to the PRYSPRY domain of TRIM21 via their Fc portions. Simultaneous binding of Fab and Fc to TRIM21 is likely to occur between distinct TRIM21 molecules via an antibody bipolar bridging mechanism, a feature of pathogenic superantigens, and form large crosslinked immune complexes.
Frank et al. (1993) determined that the TRIM21 gene contains at least 3 exons. The exon encoding the putative zinc fingers of the protein is separate from that encoding the leucine zipper.
By radioisotopic in situ hybridization, Frank et al. (1993) mapped the TRIM21 gene to chromosome 11p15.5.
Frank et al. (1993) identified a RFLP of the TRIM21 gene and demonstrated that it was associated with SLE, primarily in black Americans.
Frank, M. B., Itoh, K., Fujisaku, A., Pontarotti, P., Mattei, M.-G., Neas, B. R. The mapping of the human 52-kD Ro/SSA autoantigen gene to human chromosome 11, and its polymorphisms. Am. J. Hum. Genet. 52: 183-191, 1993. [PubMed: 8094596]
Frank, M. B. Characterization of DNA binding properties and sequence specificity of the human 52 kDa Ro/SS-A (Ro52) zinc finger protein. Biochem. Biophys. Res. Commun. 259: 665-670, 1999. [PubMed: 10364476] [Full Text: https://doi.org/10.1006/bbrc.1999.0835]
Itoh, K., Itoh, Y., Frank, M. B. Protein heterogeneity in the human Ro/SSA ribonucleoproteins: the 52- and 60-kD Ro/SSA autoantigens are encoded by separate genes. J. Clin. Invest. 87: 177-186, 1991. [PubMed: 1985094] [Full Text: https://doi.org/10.1172/JCI114968]
James, L. C., Keeble, A. H., Khan, Z., Rhodes, D. A., Trowsdale, J. Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function. Proc. Nat. Acad. Sci. 104: 6200-6205, 2007. [PubMed: 17400754] [Full Text: https://doi.org/10.1073/pnas.0609174104]
Park, J. S., Burckhardt, C. J., Lazcano, R., Solis, L. M., Isogai, T., Li, L., Chen, C. S., Gao, B., Minna, J. D., Bachoo, R., DeBerardinis, R. J., Danuser, G. Mechanical regulation of glycolysis via cytoskeleton architecture. Nature 578: 621-626, 2020. [PubMed: 32051585] [Full Text: https://doi.org/10.1038/s41586-020-1998-1]
Sjostrand, M., Carow, B., Nyberg, W. A., Covacu, R., Rottenberg, M. E., Espinosa, A. TRIM21 controls Toll-like receptor 2 responses in bone-marrow-derived macrophages. Immunology 159: 335-343, 2019. [PubMed: 31755557] [Full Text: https://doi.org/10.1111/imm.13157]