A No-Brainer! The Therapeutic Potential of TRIM Proteins in Viral and Central Nervous System Diseases

Abstract

Tripartite motif (TRIM) proteins comprise an important class of E3 ubiquitin ligases that regulate numerous biological processes including protein expression, cellular signaling pathways, and innate immunity. This ubiquitous participation in fundamental aspects of biology has made TRIM proteins a focus of study in many fields and has illuminated the negative impact they exert when functioning improperly. Disruption of TRIM function has been linked to the success of various pathogens and separately to the occurrence and development of several neurodegenerative diseases, making TRIM proteins an appealing candidate to study for novel therapeutic approaches. Here, we review the current findings on TRIM proteins that demonstrate their analogous properties in the distinct fields of viral infection and central nervous system (CNS) disorders. We also examine recent advancements in drug development and targeted protein degradation as potential strategies for TRIM-mediated therapeutic treatments and discuss the implications these technologies have on future research directions.

Keywords: CNS diseases; E3 ubiquitin ligase; PROTAC; disease therapeutic; innate immunity; protein degradation; trim-away; tripartite motif (TRIM); ubiquitin; virus infection.

Figure 1

The preventative roles of TRIM11 against tauopathies. (A) Sporadic AD brains have reduced expression of TRIM11, suggesting its importance in countering the onset of tauopathies. (B) TRIM11 can operate as a disaggregase to promote solubility of tau aggregates and fibrils. (C) TRIM11 functions as a molecular chaperone to restore misfolded tau and maintain levels of natural tau. (D) TRIM11 SUMOylates hyperphosphorylated and excess tau, marking them for proteasomal degradation. Created with BioRender.com.

Figure 2

TRIM21-based technologies for targeted protein degradation therapeutics. (A) TRIM-Away: TRIM21 binds to the Fc-region of an antibody bound to a target protein promoting the ubiquitination and proteasomal degradation of the antibody and its cargo. (B) RING-Bait: The RING domain of TRIM21 can be fused with a bait molecule consisting of an aggregate-prone tau sequence resulting in its incorporation into the assembling tau fibrils. Clustering of the RING domains promotes the ubiquitination and proteasomal degradation of tau aggregates. (C) TRIM21-based PROTACs promote interactions between TRIM21 and multimeric proteins. Substrate-induced clustering activates the E3 ubiquitin ligase function of TRIM21 to selectively degrade its multimeric targets thereby preventing protein aggregation. Created with BioRender.com.