ZYG11B, a substrate receptor of the Cullin 2-RING E3 ubiquitin ligase (CRL2), is involved in the N-degron pathway, which is crucial for protein quality control and cellular protein homeostasis [1,2,4]. It recognizes N-terminal (Nt) glycine degrons, participating in Nt-myristoylation quality control via the Gly/N-degron pathway [1,4]. Additionally, ZYG11B can recognize other small Nt-residues like Nt-Ser, -Ala, and -Cys in vitro [1]. ZYG11B also plays a role in the antiviral innate immune response by enhancing cGAS-DNA binding and condensation [3], and is associated with the modulation of colorectal cancer cell proliferation, immune infiltration, and serves as a prognostic biomarker [5].

In terms of functional studies, knockdown of ZYG11B impairs production of cGAMP and subsequent transcription of interferon and inflammatory cytokines, revealing its importance in the early stage of DNA-induced cGAS activation [3]. In colorectal cancer, bioinformatics analysis and in vitro cell experiments showed that ZYG11B has a tumor-suppressive role in cell proliferation [5]. Also, ZYG11B was found to suppress multiple enteroviruses by triggering viral VP1 degradation, highlighting its potential as a broad-spectrum antiviral target [6].

In conclusion, ZYG11B is essential for protein quality control through the N-degron pathway, and significantly impacts antiviral innate immune responses and colorectal cancer progression. Functional studies, such as knockdown experiments, have provided insights into its role in these biological processes and disease conditions, offering potential directions for future therapeutic strategies.

References:

1. Li, Yao, Zhao, Yueling, Yan, Xiaojie, Dong, Cheng, Mi, Wenyi. 2022. CRL2ZER1/ZYG11B recognizes small N-terminal residues for degradation. In Nature communications, 13, 7636. doi:10.1038/s41467-022-35169-6. https://pubmed.ncbi.nlm.nih.gov/36496439/

2. Yan, Xiaojie, Li, Yao, Wang, Guobin, Ma, Zhenyi, Dong, Cheng. 2021. Molecular basis for recognition of Gly/N-degrons by CRL2ZYG11B and CRL2ZER1. In Molecular cell, 81, 3262-3274.e3. doi:10.1016/j.molcel.2021.06.010. https://pubmed.ncbi.nlm.nih.gov/34214466/

3. Zhang, Jie, Zhou, Er-Chi, He, Yan, Zhang, Xing-Hua, Liu, Yu. 2023. ZYG11B potentiates the antiviral innate immune response by enhancing cGAS-DNA binding and condensation. In Cell reports, 42, 112278. doi:10.1016/j.celrep.2023.112278. https://pubmed.ncbi.nlm.nih.gov/36933219/

4. Timms, Richard T, Zhang, Zhiqian, Rhee, David Y, Koren, Itay, Elledge, Stephen J. . A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. In Science (New York, N.Y.), 365, . doi:10.1126/science.aaw4912. https://pubmed.ncbi.nlm.nih.gov/31273098/

5. Zhou, Jinchi, Cui, Mengmeng, Liang, Junrong, Zhao, Jing, Guo, Yanjie. 2024. ZYG11B participates in the modulation of colorectal cancer cell proliferation and immune infiltration and is a prognostic biomarker. In BMC cancer, 24, 1203. doi:10.1186/s12885-024-12963-7. https://pubmed.ncbi.nlm.nih.gov/39350118/

6. Tian, Li, Mi, Zhizhong, Yang, Weijing, Zhang, Wenyan, Li, Zhaolong. 2025. ZYG11B suppresses multiple enteroviruses by triggering viral VP1 degradation. In Journal of virology, 99, e0003025. doi:10.1128/jvi.00030-25. https://pubmed.ncbi.nlm.nih.gov/40135890/