tripartite motif containing 21

Immunopharmacology Ligand Target has curated data in GtoImmuPdb

Target id: 2967

Nomenclature: tripartite motif containing 21

Family: 2.3.2.27 RING-type E3 ubiquitin transferase

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	-	475	11p15.4	TRIM21	tripartite motif containing 21
Mouse	-	470	7 E3	Trim21	tripartite motif-containing 21
Rat	-	471	1q32	Trim21	tripartite motif-containing 21

Previous and Unofficial Names
RNF81 \| RO52 \| Ro/SSA \| Sjogren syndrome antigen A1 \| SSA1

Database Links
Alphafold	P19474 (Hs), Q62191 (Mm)
BRENDA	2.3.2.27
Ensembl Gene	ENSG00000132109 (Hs), ENSMUSG00000030966 (Mm), ENSRNOG00000018517 (Rn)
Entrez Gene	6737 (Hs), 20821 (Mm), 308901 (Rn)
Human Protein Atlas	ENSG00000132109 (Hs)
KEGG Enzyme	2.3.2.27
KEGG Gene	hsa:6737 (Hs), mmu:20821 (Mm), rno:308901 (Rn)
OMIM	109092 (Hs)
Pharos	P19474 (Hs)
RefSeq Nucleotide	NM_003141 (Hs), NM_009277 (Mm), NM_001082572 (Rn)
RefSeq Protein	NP_003132 (Hs), NP_033303 (Mm), NP_001076041 (Rn)
UniProtKB	P19474 (Hs), Q62191 (Mm)
Wikipedia	TRIM21 (Hs)

Selected 3D Structures

Image of receptor 3D structure from RCSB PDB

Description:	X-ray structure of the PRYSPRY domain of TRIM21 and IgG Fc domain.
PDB Id:	2IWG
Resolution:	2.35Å
Species:	Human
References:	3

Enzyme Reaction

EC Number: 2.3.2.27
	Description	Reaction	Reference
	Direct transfer of ubiquitin from E2 ubiquitin-conjugating enzyme to acceptor protein.	S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine <=> [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine

Immunopharmacology Comments
Tripartite motif-containing (TRIM) superfamily proteins are critical in a variety of biological processes in innate immunity and are important for eradication of invading pathogens [7-9]. The PRYSPRY domain of TRIM21 interacts with IgG Fc domains [2], and the mode of interaction identifies TRIM21 as a superantigen that may be relevant to the pathogenic accumulation of anti-TRIM21 autoantibody complexes discovered in autoimmune disease [3,6]. In the lymphocyte population, TRIM21 is mainly expressed on T cells, macrophages, and natural killer cells. TRIM21 is a component of the Ro/SSA ribonucleoprotein complex. It is implicated in the pathogensis of autoimmune diseases, including rheumatic diseases, Sjögren syndrome (SS) and systemic lupus erythematosus (SLE). Anti-Ro/SSA antibodies are more prevalent in some autoimmune diseases, including SS, SLE, antiphospholipid syndrome, systemic sclerosis and primary biliary cirrhosis [1,5-6]. A 2017 article by Zhou et al. indicates a role for TRIM21 in protection against intestinal mucosal inflammation (and by inference, inflammatory bowel diseases) via inhibition of Th1/Th17 cell differentiation [10].

Immunopharmacology Comments

Tripartite motif-containing (TRIM) superfamily proteins are critical in a variety of biological processes in innate immunity and are important for eradication of invading pathogens [7-9]. The PRYSPRY domain of TRIM21 interacts with IgG Fc domains [2], and the mode of interaction identifies TRIM21 as a superantigen that may be relevant to the pathogenic accumulation of anti-TRIM21 autoantibody complexes discovered in autoimmune disease [3,6].

In the lymphocyte population, TRIM21 is mainly expressed on T cells, macrophages, and natural killer cells. TRIM21 is a component of the Ro/SSA ribonucleoprotein complex. It is implicated in the pathogensis of autoimmune diseases, including rheumatic diseases, Sjögren syndrome (SS) and systemic lupus erythematosus (SLE). Anti-Ro/SSA antibodies are more prevalent in some autoimmune diseases, including SS, SLE, antiphospholipid syndrome, systemic sclerosis and primary biliary cirrhosis [1,5-6]. A 2017 article by Zhou et al. indicates a role for TRIM21 in protection against intestinal mucosal inflammation (and by inference, inflammatory bowel diseases) via inhibition of Th1/Th17 cell differentiation [10].

Immuno Process Associations

Immuno Process:

Barrier integrity

Immuno Process:

Inflammation

Immuno Process:

Cytokine production & signalling

Immuno Process:

Cellular signalling

General Comments
TRIM21 is proposed as a druggable anti-cancer target. In the colorectal cancer setting it ubiquitinates serine/threonine kinase 3 (MST2; STK3) and activates Hippo signaling, which has an inhibitory effect on invasion and metastasis [4]. Pharmacologically stabilising TRIM21-induced MST2 activation (using vilazodone) produces an anti-metastatic effect.

References

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1. Agmon-Levin N, Dagan A, Peri Y, Anaya JM, Selmi C, Tincani A, Bizzaro N, Stojanovich L, Damoiseaux J, Cohen Tervaert JW et al.. (2017) The interaction between anti-Ro/SSA and anti-La/SSB autoantibodies and anti-infectious antibodies in a wide spectrum of auto-immune diseases: another angle of the autoimmune mosaic. Clin Exp Rheumatol, 35 (6): 929-935. [PMID:28770708]

2. Foss S, Watkinson R, Sandlie I, James LC, Andersen JT. (2015) TRIM21: a cytosolic Fc receptor with broad antibody isotype specificity. Immunol Rev, 268 (1): 328-39. [PMID:26497531]

3. James LC, Keeble AH, Khan Z, Rhodes DA, Trowsdale J. (2007) Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function. Proc Natl Acad Sci USA, 104 (15): 6200-5. [PMID:17400754]

4. Liu YX, Wan S, Yang XQ, Wang Y, Gan WJ, Ye WL, He XS, Chen JJ, Yang Y, Yang XM et al.. (2023) TRIM21 is a druggable target for the treatment of metastatic colorectal cancer through ubiquitination and activation of MST2. Cell Chem Biol, 30 (7): 709-725.e6. [PMID:37354905]

5. Novak GV, Marques M, Balbi V, Gormezano NW, Kozu K, Sakamoto AP, Pereira RM, Terreri MT, Magalhães CS, Guariento A et al.. (2017) Anti-RO/SSA and anti-La/SSB antibodies: Association with mild lupus manifestations in 645 childhood-onset systemic lupus erythematosus. Autoimmun Rev, 16 (2): 132-135. [PMID:27988434]

6. Oke V, Wahren-Herlenius M. (2012) The immunobiology of Ro52 (TRIM21) in autoimmunity: a critical review. J Autoimmun, 39 (1-2): 77-82. [PMID:22402340]

7. Ozato K, Shin DM, Chang TH, Morse 3rd HC. (2008) TRIM family proteins and their emerging roles in innate immunity. Nat Rev Immunol, 8 (11): 849-60. [PMID:18836477]

8. Rajsbaum R, García-Sastre A, Versteeg GA. (2014) TRIMmunity: the roles of the TRIM E3-ubiquitin ligase family in innate antiviral immunity. J Mol Biol, 426 (6): 1265-84. [PMID:24333484]

9. Versteeg GA, Benke S, García-Sastre A, Rajsbaum R. (2014) InTRIMsic immunity: Positive and negative regulation of immune signaling by tripartite motif proteins. Cytokine Growth Factor Rev, 25 (5): 563-76. [PMID:25172371]

10. Zhou G, Wu W, Yu L, Yu T, Yang W, Wang P, Zhang X, Cong Y, Liu Z. (2018) Tripartite motif-containing (TRIM) 21 negatively regulates intestinal mucosal inflammation through inhibiting T_H1/T_H17 cell differentiation in patients with inflammatory bowel diseases. J Allergy Clin Immunol, 142 (4): 1218-1228.e12. [PMID:29113905]

How to cite this page

2.3.2.27 RING-type E3 ubiquitin transferase: tripartite motif containing 21. Last modified on 21/07/2023. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2967.

tripartite motif containing 21

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References

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