HYPK (huntingtin interacting protein K) is a regulatory component of N-terminal acetyltransferase (NAT) complexes that orchestrates cotranslational protein modification. It functions as both an inhibitor and activator of NAT activity: HYPK binds the NatA complex through its C-terminal ubiquitin-associated domain and N-terminal helix, blocking NatA catalytic activity in vitro while simultaneously preventing ribosomal release of inhibitory interactions that suppress NatA activation 12. Recent structural studies reveal that NAC (nascent polypeptide-associated complex) coordinates HYPK interactions to release this inhibition and enforce cotranslational N-terminal acetylation during protein synthesis 3. Beyond NAT regulation, HYPK functions as an autophagy receptor that coordinates degradation of proteotoxic protein aggregates through NEDD8 conjugation, protecting cells from polyglutamine aggregates including mutant huntingtin 4. HYPK exhibits intrinsic chaperone-like activity that reduces polyglutamine aggregation in neuronal cells 5, and its expression is induced by cellular stress through Heat Shock Factor 1 transcriptional control 6. The gene's regulatory complexity reflects its dual role: controlling the fate of approximately 40% of the mammalian proteome through N-terminal acetylation while simultaneously managing proteostasis under stress conditions.