CRL3s: The BTB-CUL3-RING E3 Ubiquitin Ligases

The ubiquitin proteasome pathway is one of the major regulatory tools used by eukaryotic cells. The evolutionarily conserved cullin family proteins can assemble as many as >600 distinct E3 ubiquitin ligase complexes that regulate diverse cellular pathways. In most of Cullin-RING ubiquitin ligase (CRL) complexes, separate linker and adaptor proteins build the substrate recognition module. Differently, a single BTB-containing adaptor molecule utilizing two protein interaction sites can link the CUL3 scaffold to the substrate, forming as many as 188 CUL3-BTB E3 ligase complexes in mammals. Here, we review the most recent studies on CRL3 complexes, with a focus on the model for CUL3 assembly with its BTB-containing substrate receptors. Also, we summarize the current knowledge of CRL3 substrates and their relevant biological functions. Next, we discuss the mutual exclusivity of somatic mutations in KEAP1, NRF2, and CUL3 in human lung cancer. Finally, we highlight new strategies to expand CUL3 substrates and discuss outstanding questions remaining in the field.