HYPK (huntingtin interacting protein K) is a multifunctional regulatory protein that serves as a key modulator of N-terminal protein acetylation and proteostasis. HYPK functions as a component of N-terminal acetyltransferase complexes, particularly the NatA complex, where it exhibits dual regulatory roles 1. While HYPK inhibits NatA activity in vitro through its bipartite structure - a ubiquitin-associated domain that binds NAA15 and an N-terminal loop-helix region that distorts the NAA10 active site 1 - it paradoxically enhances NatA function in vivo by acting as a ribosome exchange factor 2. This mechanism allows NatA to dissociate from ribosomes and access additional translation sites, enabling efficient acetylation of ~40% of the proteome 2. Beyond acetylation regulation, HYPK functions as an autophagy receptor for polyneddylated protein aggregates, coordinating their degradation through its LC3-interacting region and protecting cells from proteotoxicity 3. HYPK also exhibits chaperone-like activity, preventing polyglutamine aggregation of huntingtin in neuronal cells 4. The protein is stress-responsive, being upregulated by heat shock factor 1 during cellular stress conditions 5, highlighting its importance in cellular protection mechanisms.