Redirecting TRIM21 with TRIMTACs for the targeted degradation of multimeric proteins.

PROTACs (PROteolysis-Targeting Chimeras) are heterobifunctional small molecules that induce proximity between E3 ubiquitin ligases and target proteins to drive target protein ubiquitination and proteasomal degradation. TRIM21 is an intracellular Immunoglobulin G (IgG) receptor and E3 ubiquitin ligase that functions to degrade cytoplasmic antibody-coated viral particles. Genetic approaches have redirected TRIM21 towards a wide range of cellular proteins, and mechanistic studies have demonstrated TRIM21's preference for degrading multimeric substrates such as protein aggregates. Recently, the first small molecules targeting TRIM21 have been reported, including some that have been elaborated into PROTACs (TRIMTACs) that degrade multimeric proteins. In this State-of-the-Art review, we describe the unique biology of TRIM21, detail recently reported TRIMTACs, and suggest future opportunities for TRIMTACs to impact targeted protein degradation.