TRIM family proteins and their emerging roles in innate immunity

Abstract

The TRIM (tripartite motif-containing) family of proteins is defined by an amino-terminal set of domains that is known as the RBCC (RING, B-box, coiled-coil) motif. The RBCC motif can exist in isolation or in combination with various carboxy-terminal domains. The RING domain of many TRIM proteins has E3 ubiquitin ligase activity that can mediate autoubiquitylation and, less often, sumoylation or ISGylation of the TRIM protein itself and other proteins. The coiled-coil domain promotes self-association and protein oligomerization that can trigger the formation of large protein complexes that are localized to the nucleus or the cytoplasm. Mutations in the TRIM genes MID1 (midline 1), TRIM32 and TRIM37 are responsible for the hereditary genetic diseases X-linked Opitz G/BBB syndrome, limb-girdle muscular dystrophy (type 2H) and Mulibrey nanism, respectively. Many TRIM proteins are responsive to interferon (IFN), with some functioning as downstream effectors of IFN in innate immune responses to retroviruses and other viruses. Members with anti-HIV activity can impede the life cycle of the virus before integration (for example, TRIM5), transcription (for example, TRIM22, TRIM32) and assembly (for example, TRIM22 and TRIM15). Products of other TRIM genes — TRIM21, TRIM25, TRIM27, TRIM30 and TRIM32 — function downstream of IFN and of pathogen-recognition receptors, and modulate innate immune responses to bacterial and viral infections that involve the activation of IFN-regulatory factor 3 (IRF3), IRF7 and nuclear factor-κB (NF-κB). Two TRIM proteins, TRIM21 and TRIM68, are prominent targets of autoantibodies in patients with systemic lupus erythematosus or Sjögren's syndrome.