HYPK promotes the activity of the <i>N</i> <sup>α</sup> -acetyltransferase A complex to determine proteostasis of nonAc-X <sup>2</sup> /N-degron–containing proteins
Pavlína Miklánková, Eric Linster, J. Boyer, Jonas Weidenhausen, Johannes Müller, Laura Armbruster, Karine Lapouge, Carolina De La Torre, Willy V. Bienvenut, Carsten Sticht, Matthias Mann, Thierry Meinnel, Irmgard Sinning, Carmela Giglione, Rüdiger Hell, Markus Wirtz
Abstract
In humans, the Huntingtin yeast partner K (HYPK) binds to the ribosome-associated N α -acetyltransferase A (NatA) complex that acetylates ~40% of the proteome in humans and Arabidopsis thaliana . However, the relevance of Hs HYPK for determining the human N-acetylome is unclear. Here, we identify the At HYPK protein as the first in vivo regulator of NatA activity in plants . At HYPK physically interacts with the ribosome-anchoring subunit of NatA and promotes N α -terminal acetylation of diverse NatA substrates. Loss-of- At HYPK mutants are remarkably resistant to drought stress and strongly resemble the phenotype of NatA-depleted plants. The ectopic expression of Hs HYPK 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.