TRIM Family Proteins: Roles in Autophagy, Immunity, and Carcinogenesis

Ubiquitination is catalyzed by the E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases, which are a critical component directly responsible for substrate recognition. Tripartite motif (TRIM) proteins, more than 80 being present in humans, are defined as a subfamily of the RING-type E3 ubiquitin ligase family. In autophagy several TRIM proteins function as platforms for the assembly of autophagy regulators and recognize targets such as ubiquitinated cargos via sequestosome-1-like receptors. Some TRIM proteins positively or negatively control many regulators including pattern recognition receptors, intracellular signal transducers and transcription factors in innate immunity. TRIM proteins are involved in a broad range of oncogenic processes including transcriptional regulation, cell proliferation, apoptosis, DNA repair, and metastasis. Tripartite motif (TRIM) family proteins, most of which have E3 ubiquitin ligase activities, have various functions in cellular processes including intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis. The ubiquitin system is one of the systems for post-translational modifications, which play crucial roles not only as markers for degradation of target proteins by the proteasome but also as regulators of protein–protein interactions and of the activation of enzymes. Accumulating evidence has shown that TRIM family proteins have unique, important roles and that their dysregulation causes several diseases classified as cancer, immunological disease, or developmental disorders. In this review we focus on recent emerging topics on TRIM proteins in the regulation of autophagy, innate immunity, and carcinogenesis. Tripartite motif (TRIM) family proteins, most of which have E3 ubiquitin ligase activities, have various functions in cellular processes including intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis. The ubiquitin system is one of the systems for post-translational modifications, which play crucial roles not only as markers for degradation of target proteins by the proteasome but also as regulators of protein–protein interactions and of the activation of enzymes. Accumulating evidence has shown that TRIM family proteins have unique, important roles and that their dysregulation causes several diseases classified as cancer, immunological disease, or developmental disorders. In this review we focus on recent emerging topics on TRIM proteins in the regulation of autophagy, innate immunity, and carcinogenesis. an enzyme in the first step of the ubiquitin-conjugation reaction. E1 activates ubiquitin by adenylation with ATP and the carboxyl group of ubiquitin and by linking the carboxy-terminal glycine of ubiquitin to the sulfhydryl side chain moiety of a cysteine of E1. an enzyme that has a core catalytic domain required for transferring ubiquitin from E1 and forms a thioester bond with ubiquitin via the sulfhydryl side chain moiety of a cysteine of E2 itself. an enzyme that performs the conjugation of ubiquitin to a lysine on a target protein through an isopeptide bond in collaboration with an E2 ubiquitin-conjugating enzyme. E3 ubiquitin ligase recognizes specific protein substrates and is involved in several types of polyubiquitination using seven amino groups of lysine or the amino-terminal methionine of ubiquitin. a protein complex for polyubiquitin-mediated degradation that functions in the nucleus and cytoplasm. The proteasome is present in Archaebacteria and all eukaryotes. a structural domain of zinc-finger-type proteins that has a Cys3HisCys4 or Cys3His2Cys3 amino acid motif containing two zinc ions. This protein domain usually has approximately 40–60 amino acids. Proteins containing a RING-finger domain generally play a role in E3 ubiquitin ligase activity. a protein structure comprising a RING-finger domain, a B1-box and/or a B2-box domain, and a coiled-coil region. a small protein that contains 76 amino acids and is highly conserved among eukaryotic species. Ubiquitin on target proteins plays roles as a marker for proteasome-mediated degradation and as a marker for endocytosis, DNA repair, and enzymatic activation.