TRIM21/Ro52 - Roles in Innate Immunity and Autoimmune Disease

Abstract

TRIM21 (Ro52/SSA1) is an E3 ubiquitin ligase with key roles in immune host defence, signal transduction, and possibly cell cycle regulation. It is also an autoantibody target in Sjögren's syndrome, systemic lupus erythematosus, and other rheumatic autoimmune diseases. Here, we summarise the structure and function of this enzyme, its roles in innate immunity, adaptive immunity and cellular homeostasis, the pathogenesis of autoimmunity against TRIM21, and the potential impacts of autoantibodies to this intracellular protein.

Keywords: E3 ubiquitin ligase; Fc receptor; Sjogren’s syndrome; autoimmune disease; innate immunity; intracellular antibodies; systemic lupus erythematosus.

Figure 1

TRIM21 structure includes RING, B-box, coiled-coil and PRY/SPRY domains. (A) Dimerised TRIM21 cartoon shows binding of PRY/SPRY domain at constant region (Fc) of antibody. Dimerisation at the coiled-coil is predicted according to homology to other TRIM family members. Phosphorylation of the LxxIS motif of the RING domain relieves B-box inhibition, allowing RING dimerisation for catalytic activity. (B) X-ray crystallography structures have been obtained for the (1) PRY/SPRY domain, identified in complex with the Fc antibody domain (PDB:2IWG) (25). (2) The B-box and RING domains have been crystallised in a dimer confirmation (PDB:5OLM) (26). The central predicted coiled-coil structure has not been formally identified.

Figure 2

(A) TRIM21 in antiviral responses. TRIM21 is recruited to cytosolic antibody-bound-Ad5 after virus entry into the cell. Ad5 binds to CAR/αv integrin receptors at the cell surface, triggering capsid disassembly upon cell entry. Lytic protein VI is released leading to endosomal disassembly and “endosomal escape” of the antibody-bound-Ad5. Active, ubiquitinated TRIM21 binds to the Fc region of the antibody and promotes subsequent proteasomal degradation. (B) TRIM21 in responses to intracellular bacteria. TRIM21 is recruited to antibody-coated SifA-mutant S. typhimurium. Wild-type S. typhimurium are protected from TRIM21-mediated degradation due to the presence of vATPase and lgps, which maintain SCV integrity and enable endosome fusion for bacterial replication. ΔSifA bacteria cannot maintain SCV integrity, leading to endosomal escape into the cytosol for TRIM21-mediated degradation.

Figure 3

TRIM21 and IFN signalling. (A) TRIM21 expression is upregulated by IFN-I and IFN-II signalling. IFN-I signalling involves JAK/STAT phosphorylation and ISGF3 complex formation for early IRF expression. Nuclear translocation of IRF1/2 and binding to the ISRE leads to expression of IFN-stimulated genes including TRIM21. IFN-II signalling also occurs via JAK/STAT signalling, leading to formation of the GAF complex. This binds to GAS elements for IRF1 expression and subsequent TRIM21 expression. TRIM21 upregulation is inhibited by IRF4 and IRF8, although much of the upstream signalling pathway remains to be fully elucidated. (B) After upregulation, TRIM21 downregulates the IFN-I response via ubiquitination of IRF7, IRF5 and possibly IRF3. (C) TRIM21 enhances proinflammatory macrophage cytokine expression after IRF8 ubiquitination.

Figure 4

Absence or deficiencies in TRIM21 may alter the IRF4/5 axis. TRIM21 regulates IRF5 via ubiquitination, potentially affecting downstream IRF4 and Blimp-1 expression. Aberrant regulation may increase differentiation of antibody-secreting plasma cells.

Figure 5

TRIM21 exposure at the cell surface may occur due to apoptosis. In foetal CHB, cross-reactive maternal autoantibodies may bind to and block L-type calcium channels leading to arrhythmia and cardiomyocyte apoptosis. This releases intracellular antigens such as TRIM21 for antigen presentation, driving subsequent autoimmunity.