K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution

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  • Aldwin Suryo Rahmanto
  • Christian J. Blum
  • Claudia Scalera
  • Jan B. Heidelberger
  • Mikhail Mesitov
  • Daniel Horn-Ghetko
  • Ivan Mikicic
  • Rebecca Hobrecht
  • Anna Orekhova
  • Matthias Ostermaier
  • Stefanie Ebersberger
  • Martin M. Möckel
  • Nils Krapoth
  • Nádia Da Silva Fernandes
  • Athanasia Mizi
  • Yajie Zhu
  • Jia Xuan Chen
  • Argyris Papantonis
  • Helle D. Ulrich
  • Brenda A. Schulman
  • Julian König
  • Petra Beli

Reactive aldehydes are produced by normal cellular metabolism or after alcohol consumption, and they accumulate in human tissues if aldehyde clearance mechanisms are impaired. Their toxicity has been attributed to the damage they cause to genomic DNA and the subsequent inhibition of transcription and replication. However, whether interference with other cellular processes contributes to aldehyde toxicity has not been investigated. We demonstrate that formaldehyde induces RNA-protein crosslinks (RPCs) that stall the ribosome and inhibit translation in human cells. RPCs in the messenger RNA (mRNA) are recognized by the translating ribosomes, marked by atypical K6-linked ubiquitylation catalyzed by the RING-in-between-RING (RBR) E3 ligase RNF14, and subsequently resolved by the ubiquitin- and ATP-dependent unfoldase VCP. Our findings uncover an evolutionary conserved formaldehyde-induced stress response pathway that protects cells against RPC accumulation in the cytoplasm, and they suggest that RPCs contribute to the cellular and tissue toxicity of reactive aldehydes.

Original languageEnglish
JournalMolecular Cell
Issue number23
Pages (from-to)4272-4289.e10
Number of pages29
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

    Research areas

  • K6-linked ubiquitylation, quantitative proteomics, reactive aldehydes, ribosome, RNA-protein crosslinks, RNF14, translation, VCP

ID: 378949358