Conserved structural and functional aspects of the tripartite motif gene family point towards therapeutic applications in multiple diseases

Abstract

The tripartite motif (TRIM) gene family is a highly conserved group of E3 ubiquitin ligase proteins that can establish substrate specificity for the ubiquitin-proteasome complex and also have proteasome-independent functions. While several family members were studied previously, it is relatively recent that over 80 genes, based on sequence homology, were grouped to establish the TRIM gene family. Functional studies of various TRIM genes linked these proteins to modulation of inflammatory responses showing that they can contribute to a wide variety of disease states including cardiovascular, neurological and musculoskeletal diseases, as well as various forms of cancer. Given the fundamental role of the ubiquitin-proteasome complex in protein turnover and the importance of this regulation in most aspects of cellular physiology, it is not surprising that TRIM proteins display a wide spectrum of functions in a variety of cellular processes. This broad range of function and the highly conserved primary amino acid sequence of family members, particularly in the canonical TRIM E3 ubiquitin ligase domain, complicates the development of therapeutics that specifically target these proteins. A more comprehensive understanding of the structure and function of TRIM proteins will help guide therapeutic development for a number of different diseases. This review summarizes the structural organization of TRIM proteins, their domain architecture, common and unique post-translational modifications within the family, and potential binding partners and targets. Further discussion is provided on efforts to target TRIM proteins as therapeutic agents and how our increasing understanding of the nature of TRIM proteins can guide discovery of other therapeutics in the future.

TRIM59 as a novel molecular biomarker to predict the prognosis of patients with NSCLC

“…In the past decade, the role of TRIM proteins in the innate immunity response to viral infection has attracted increasing attention (24)(25)(26). Previous studies have demonstrated that TRIM proteins are involved in several cell functions and participate in the process of ubiquitination as E3 ubiquitin ligases (27,28). For example, TRIM59 was revealed to regulate autophagy by regulating the transcription and ubiquitination of beclin 1, which in turn affected the progression of NSCLC (29).…”

The Tripartite Nexus: Autophagy, Cancer, and Tripartite Motif-Containing Protein Family Members

“…RING, B-box, coiled-coil, FN3, SPRY, bromobox/bromodomain, etc.) (Gushchina et al, 2018). One approach to drug design would be to target the activity of specific domains critical to TRIM function in cancer.…”

Emerging Role of TRIM Family Proteins in Cardiovascular Disease

“…Growing evidence suggests that MuRF1 acts on troponin I, negatively regulating cardiac hypertrophic effects, with its upregulation leading to a loss of muscle mass and impaired myocardium contractility, decreased protein synthesis, and enhanced protein degradation through UPS, which then causes heart failure [59][60][61][62][63][64]. Ectopic expression of the mutant TRIM63/MuRF1 has been reported to cause the mislocalization and impaired ubiquitination as well as the hypertrophy of cardiomyocytes.…”