ZYG11B is a substrate adapter for the CRL2 E3 ubiquitin ligase complex that targets proteins bearing N-terminal degrons for proteasomal degradation 1. The complex preferentially recognizes N-terminal glycine residues, with the first four amino acids of substrates serving as the primary recognition elements, though ZYG11B also accepts N-terminal serine, alanine, and cysteine 2. Structurally, ZYG11B utilizes armadillo repeats forming a deep cavity that accommodates degrons through conserved hydrogen bonds 2. ZYG11B functions in multiple biological contexts. During apoptosis, it mediates clearance of proteolytic fragments generated by caspase cleavage, as N-terminal glycine degrons are enriched at caspase cleavage sites 1. It participates in quality control of N-myristoylation by degrading proteins when myristoylation fails 1. ZYG11B amplifies innate immune responses by enhancing cGAS-DNA binding, oligomerization, and condensation to potentiate antiviral interferon production 3. Additionally, ZYG11B suppresses enterovirus replication by targeting viral VP1 protein for degradation via K33-linked ubiquitination 4. Clinically, ZYG11B demonstrates tumor-suppressive functions in colorectal cancer, with reduced expression correlating with poor prognosis and increased proliferation 5. Its substrate specificity makes it a promising platform for targeted protein degradation therapeutics, including PROTACs and aptamer-based approaches 67.