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.