Proteolytic dissection of eIF4G reveals that closed-loop mRNP formation is dispensable for bulk translation in mammalian cells.

Acute depletion of eIF4G1 in mammalian cells only partially reduces global translation, and bulk protein synthesis recovers without restoring eIF4G1 levels.

• Why it matters: The closed-loop model predicts cap–poly(A) bridging via eIF4E–eIF4G–PABP is needed for efficient translation, but direct tests in mammalian cells have been lacking.
• What they did: Using auxin-inducible degrons to deplete eIF4G1, the study assessed translation after loss, mapped contributions from eIF4G3, and used eIF4G1 and PABP perturbations plus the N-terminal enteroviral cleavage product 2A-cp N.
• The result: eIF4G3 buffers translation during eIF4G1 loss; eIF4G1 PABP binding is dispensable for bulk synthesis, PABP depletion destabilizes poly(A) mRNA, and 2A-cp N potently represses translation via PABP- and eIF4E-binding domains.

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