Ribosome-NAC collaboration: A regulatory platform for cotranslational chaperones, enzymes, and targeting factors

Protein biogenesis requires the ribosome to collaborate with a diverse set of cotranslational factors that shape the fate of nascent chains. These interactions must be precisely choreographed: while cytonuclear proteins require immediate N-terminal maturation and folding, endoplasmic reticulum (ER) and mitochondrial proteins must be maintained in an unfolded state for targeting to their organelles. Reconciling these opposing demands requires a highly selective sorting mechanism operating at the ribosomal exit tunnel. Recent studies identify the conserved nascent polypeptide-associated complex (NAC) as a central coordinator of this process. By sensing nascent signals and dynamically modulating factor access to the ribosome, NAC directs substrates toward the appropriate maturation or targeting pathway. This emerging framework positions NAC as a molecular hub that organizes cotranslational interactions into efficient and orderly protein-biogenesis pathways. In this review, we discuss the mechanistic principles underlying NAC function and consider broader implications for how ribosome-associated networks enforce fidelity in protein biogenesis. How do ribosomes direct nascent chains toward folding or organelle targeting? This review outlines emerging mechanisms by which the nascent polypeptide-associated complex (NAC) decodes early signals at the ribosomal tunnel and orchestrates the selective engagement of cotranslational factors to maintain fidelity in protein biogenesis.