K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution
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K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution. / Suryo Rahmanto, Aldwin; Blum, Christian J.; Scalera, Claudia; Heidelberger, Jan B.; Mesitov, Mikhail; Horn-Ghetko, Daniel; Gräf, Justus F.; Mikicic, Ivan; Hobrecht, Rebecca; Orekhova, Anna; Ostermaier, Matthias; Ebersberger, Stefanie; Möckel, Martin M.; Krapoth, Nils; Da Silva Fernandes, Nádia; Mizi, Athanasia; Zhu, Yajie; Chen, Jia Xuan; Choudhary, Chunaram; Papantonis, Argyris; Ulrich, Helle D.; Schulman, Brenda A.; König, Julian; Beli, Petra.
In: Molecular Cell, Vol. 83, No. 23, 2023, p. 4272-4289.e10.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution
AU - Suryo Rahmanto, Aldwin
AU - Blum, Christian J.
AU - Scalera, Claudia
AU - Heidelberger, Jan B.
AU - Mesitov, Mikhail
AU - Horn-Ghetko, Daniel
AU - Gräf, Justus F.
AU - Mikicic, Ivan
AU - Hobrecht, Rebecca
AU - Orekhova, Anna
AU - Ostermaier, Matthias
AU - Ebersberger, Stefanie
AU - Möckel, Martin M.
AU - Krapoth, Nils
AU - Da Silva Fernandes, Nádia
AU - Mizi, Athanasia
AU - Zhu, Yajie
AU - Chen, Jia Xuan
AU - Choudhary, Chunaram
AU - Papantonis, Argyris
AU - Ulrich, Helle D.
AU - Schulman, Brenda A.
AU - König, Julian
AU - Beli, Petra
N1 - Publisher Copyright: © 2023 The Author(s)
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - K6-linked ubiquitylation
KW - quantitative proteomics
KW - reactive aldehydes
KW - ribosome
KW - RNA-protein crosslinks
KW - RNF14
KW - translation
KW - VCP
U2 - 10.1016/j.molcel.2023.10.011
DO - 10.1016/j.molcel.2023.10.011
M3 - Journal article
C2 - 37951215
AN - SCOPUS:85178169389
VL - 83
SP - 4272-4289.e10
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 23
ER -
ID: 378949358