TRIM21
Description
The TRIM21 (tripartite motif containing 21) is a protein-coding gene located on chromosome 11.
Tripartite motif-containing protein 21 (TRIM21), also known as E3 ubiquitin-protein ligase TRIM21, is a protein encoded by the TRIM21 gene in humans. Multiple transcript variants have been described for this gene, but only one has been fully characterized. TRIM21 is expressed in most human tissues. TRIM21 is a member of the tripartite motif (TRIM) family, characterized by three zinc-binding domains: a RING finger domain, a B-box type 1, and a B-box type 2 zinc finger, along with a coiled coil region. TRIM21 functions as an intracellular antibody effector in the intracellular antibody-mediated proteolysis pathway. It binds to the Fc domain of immunoglobulins G, A, and M on antibody-marked non-enveloped virions that have infected cells. This binding triggers either autoubiquitination or ubiquitination of a cofactor, directing the virions to the proteasome for degradation. Importantly, TRIM21 itself is not degraded, unlike the viral capsid and the bound antibody. TRIM21 is also a component of the RoSSA ribonucleoprotein complex, which includes a single polypeptide and one of four small RNA molecules.
TRIM21 is an E3 ubiquitin-protein ligase whose activity relies on E2 enzymes like UBE2D1, UBE2D2, UBE2E1, and UBE2E2. It forms a ubiquitin ligase complex with E2 UBE2D2, which is involved in the ubiquitination of USP4 and IKBKB as well as self-ubiquitination. TRIM21 is part of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. A TRIM21-containing SCF(SKP2)-like complex ubiquitinates CDKN1B (phosphorylated at 'Thr-187'), leading to its proteasomal degradation. TRIM21 monoubiquitinates IKBKB, negatively regulating Tax-induced NF-kappa-B signaling. It also negatively regulates IFN-beta production following pathogen recognition by degrading IRF3 through polyubiquitination. TRIM21 mediates the proteasomal degradation of IgG1 heavy chain via ubiquitination, linked to the VCP-mediated ER-associated degradation (ERAD) pathway. It promotes IRF8 ubiquitination, enhancing IRF8's ability to stimulate cytokine gene transcription in macrophages. TRIM21 plays a role in cell cycle regulation, enhances the decapping activity of DCP2, and exists as a ribonucleoprotein particle in all mammalian cells, composed of a single polypeptide and one of four small RNA molecules. At least two isoforms exist in nucleated and red blood cells, with tissue-specific variations in RO/SSA proteins. These proteins are characterized by their ability to bind HY RNAs.2. TRIM21 is involved in regulating innate immunity and the inflammatory response to IFNG/IFN-gamma. It serves as a platform for assembling ULK1, Beclin 1/BECN1, and ATG8 family members during autophagy, coordinating target recognition with the assembly of the autophagic apparatus and autophagy initiation. It also regulates autophagy through FIP200/RB1CC1 ubiquitination, decreasing protein stability. TRIM21 represses the innate antiviral response by facilitating the formation of the NMI-IFI35 complex through 'Lys-63'-linked ubiquitination of NMI. During viral infection, TRIM21 promotes cell pyroptosis by ubiquitinating ISG12a/IFI27 with 'Lys-6'-linked ubiquitination, facilitating its translocation to the mitochondria and subsequent CASP3 activation. When upregulated through the IFN/JAK/STAT signaling pathway, TRIM21 promotes 'Lys-27'-linked ubiquitination of MAVS, leading to TBK1 recruitment and enhanced innate immunity. TRIM21 mediates 'Lys-63'-linked polyubiquitination of G3BP1 in response to heat shock, leading to stress granule disassembly. TRIM21 exists as a homotrimer and interacts with IRF8 (via its C-terminus), forming a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21, and SKP2. TRIM21 interacts with CALR, CUL1, FBXW11, HSPA5, IKBKB, IRF3, SKP1, and VCP. Its interaction with SKP2 is independent of an intact F-box domain. TRIM21 interacts with DCP2 (via its N-terminus and C-terminus), ULK1, BECN1, and ATG8 family members, including GABARAP, GABARAPL1, GABARAPL2, and MAP1LC3C/LC3C. It also interacts with TRIM21 and SQSTM1/sequestosome 1, and IRF3. TRIM21 interacts (via its SPRY domain) with NMI (via its coiled-coil domain), promoting 'Lys-63'-linked ubiquitination of NMI. This interaction facilitates the formation of the NMI-IFI35 complex. During microbial infection, TRIM21 interacts (via its B30.2/SPRY domain) with severe fever with thrombocytopenia syndrome virus (SFTSV) NSs, activating NFE2L2-mediated transcriptional activation of antioxidant genes.
TRIM21 is also known as RNF81, RO52, Ro/SSA, SSA, SSA1.
