ZYG11B, a substrate receptor of the Cullin 2-RING E3 ubiquitin ligase (CRL2), plays a vital role in the Gly/N-degron pathway, which is part of the N-degron pathways involved in protein quality control and cellular protein homeostasis [1,2,4,7]. It recognizes N-terminal glycine degrons, contributing to the quality control of N-myristoylated proteins [4]. Moreover, it has been implicated in innate immune responses, as well as in regulating cell proliferation in certain cancers [3,5].

In antiviral innate immune responses, knockdown of ZYG11B impairs the production of cyclic GMP-AMP (cGAMP) and subsequent transcription of interferon and inflammatory cytokines. Mechanistically, it enhances cGAS-DNA binding affinity, potentiates cGAS-DNA condensation, and stabilizes the cGAS-DNA condensed complex [3]. In colorectal cancer, ZYG11B exhibits a tumor-suppressive role, as its expression is diminished in cancer tissues compared to adjacent normal tissues. Functional assays show that it suppresses the progression of colorectal cancer cells, and its increased expression correlates with enhanced survival rates [5]. Additionally, ZYG11B can target the structural protein VP1 of enteroviruses for proteasomal degradation, restricting the growth of multiple enteroviruses [6].

In conclusion, ZYG11B is essential for protein quality control through the Gly/N-degron pathway. Its role in antiviral innate immune responses and colorectal cancer cell proliferation regulation, as revealed by functional studies, provides valuable insights into the underlying biological processes and potential disease-related mechanisms. The study of ZYG11B offers new perspectives for understanding disease occurrence and developing therapeutic strategies for related diseases such as certain viral infections and colorectal cancer.