HYPK promotes the activity of the Nα-acetyltransferase A complex to determine proteostasis of nonAc-X2/N-degron-containing proteins

In humans, the Huntingtin yeast partner K (HYPK) binds to the ribosome-associated N.-acetyltransferase A (NatA) complex that acetylates similar to 40% of the proteome in humans and Arabidopsis thaliana. However, the relevance of HsHYPK for determining the human N-acetylome is unclear. Here, we identify the AtHYPK protein as the first in vivo regulator of NatA activity in plants. AtHYPK physically interacts with the ribosome-anchoring subunit of NatA and promotes N.-terminal acetylation of diverse NatA substrates. Loss-of-AtHYPK mutants are remarkably resistant to drought stress and strongly resemble the phenotype of NatA-depleted plants. The ectopic expression of HsHYPK rescues this phenotype. Combined transcriptomics, proteomics, and N-terminomics unravel that HYPK impairs plant metabolism and development, predominantly by regulating NatA activity. We demonstrate that HYPK is a critical regulator of global proteostasis by facilitating masking of the recently identified nonAc-X-2/N-degron. This N-degron targets many nonacetylated NatA substrates for degradation by the ubiquitin-proteasome system.

Automated summary

This study identifies AtHYPK protein as the first in vivo regulator of NatA activity in plants, which interacts with the ribosome-anchoring subunit of NatA and promotes N-terminal acetylation of various substrates. Loss-of-AtHYPK mutants exhibit remarkable resistance to drought stress and resemble the phenotype of NatA-depleted plants. HYPK regulates plant metabolism and development by modulating NatA activity, and plays a critical role in global proteostasis.