4.8 Article

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

Journal

SCIENCE ADVANCES
Volume 8, Issue 24, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abn6153

Keywords

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Funding

  1. Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [201348542, SFB 1036, WI 3560/4-1, WI 3560/7-1, DFG-IS-586/6-1]
  2. French Agence Nationale de la Recherche [ANR-13-BSV6-0004, ANR-17-CAPS-0001-01]
  3. Labex Saclay Plant Sciences SPS [ANR-10-LABX-0040-SPS]
  4. IBiSA
  5. Ile de France Region
  6. Plan Cancer
  7. CNRS
  8. Paris-Saclay University
  9. Agence Nationale de la Recherche (ANR) [ANR-17-CAPS-0001] Funding Source: Agence Nationale de la Recherche (ANR)

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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.
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.

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