The many faces of the GID/CTLH E3 ligase complex.

The GID/C-terminal to LisH (CTLH) E3 is an emerging family of evolutionarily conserved multiprotein E3 ligase complexes implicated in various biological processes including metabolic rewiring, stress-responsive regulation, cellular differentiation, and immunity. Pioneering biochemical reconstitution, cryo-EM, and cell-based studies have illuminated many aspects of the compositional and structural dynamics of GID/CTLH E3 complexes. GID/CTLH E3 undergoes sophisticated regulation through incorporation of interchangeable substrate receptors and association with supramolecular assembly factors enabling higher-order complex formation. Furthermore, paralogous subunits vary and may modulate function across cell types. Additionally, an assortment of regulatory factors fine-tune substrate selection, underscoring the adaptability of this E3 ligase system. Here, we review these distinct ubiquitin ligase features, examine the mechanistic implications of GID/CTLH E3 regulation and the exquisite targeting of oligomeric substrates, and discuss potential for therapeutic application in targeted protein degradation.