TRIM21 belongs to the RING E3 ubiquitin ligases family, and TRIM subfamily. Its activity is dependent on E2 enzymes. It is a part of the cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin protein-ligase complexes.
Known substrates of TRIM21 include ubiquitin specific protease 4 (USP4), IKBKB, interferon regulatory factor (IRF) 3, IRF5, IRF7, and IRF8. It is involved in negative regulation of nuclear factor kappa B (NFkB) signalling, interferon (IFN)-β production; enhances cytokine production in macrophages, plays a role in the regulation of the cell cycle progression.