NITAC-mediated ISGylation of eIF4E2 attenuates GSK3β proline-directed kinase activity, conferring cytoprotection.

ABSTRACT: Eukaryotic translation initiation factor 4E family member 2 (eIF4E2) has recently been identified as an interacting protein of GSK3β and regulates its proline-directed kinase activity. eIF4E2 undergoes ISGylation at K134 and K222, a conserved posttranslational modification mediated by interferon-stimulated gene 15. In this study, we engineered a novel Nanobody-based ISGylation Targeting Chimera (NITAC) tool to specifically activate eIF4E2 ISGylation and investigate its role in the eIF4E2-GSK3β signaling pathway. By integrating eIF4E2-specific nanobodies Nb.30C7 with the catalytic E3 ligase domain HECT from HERC5, we constructed the NITAC (Nb.30C7-HECT). This NITAC tool mediates site-specific ISGylation of eIF4E2, enhancing the eIF4E2-GSK3β interaction and unexpectedly suppressing proline-d

SUBMITTER: Li L 

PROVIDER: S-EPMC12607020 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature