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The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation.

Genome Biol.2019 Oct 22;20(1):216
Andrea Hildebrandt 1 , Mirko Brüggemann 2 , Cornelia Rücklé 2 , Susan Boerner 2 , Jan B Heidelberger 1 , Anke Busch 1 , Heike Hänel 1 , Andrea Voigt 1 , Martin M Möckel 1 , Stefanie Ebersberger 1 , Anica Scholz 3 , Annabelle Dold 1 , Tobias Schmid 3 , Ingo Ebersberger 4 , Jean-Yves Roignant 5 , Kathi Zarnack 6 , Julian König 7 , Petra Beli 8
Andrea Hildebrandt 1 , Mirko Brüggemann 2 , Cornelia Rücklé 2 , Susan Boerner 2 , Jan B Heidelberger 1 , Anke Busch 1 , Heike Hänel 1 , Andrea Voigt 1 , Martin M Möckel 1 , Stefanie Ebersberger 1 , Anica Scholz 3 , Annabelle Dold 1 , Tobias Schmid 3 , Ingo Ebersberger 4 , Jean-Yves Roignant 5 , Kathi Zarnack 6 , Julian König 7 , Petra Beli 8
+ et al

[No authors listed]

Author information
  • 1 Institute of Molecular Biology (IMB), Ackermannweg 4, 55128, Mainz, Germany.
  • 2 Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University, Max-von-Laue-Str. 15, 60438, Frankfurt am Main, Germany.
  • 3 Faculty of Medicine, Institute of Biochemistry I, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
  • 4 Senckenberg Biodiversity and Climate Research Centre (BiK-F), Georg-Voigt-Straße 14-16, 60325, Frankfurt am Main, Germany.
  • 5 Center for Integrative Genomics, Faculty of Biology and Medicine, University of Lausanne, Génopode Building, CH-1015, Lausanne, Switzerland.
  • 6 Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University, Max-von-Laue-Str. 15, 60438, Frankfurt am Main, Germany. kathi.zarnack@bmls.de.
  • 7 Institute of Molecular Biology (IMB), Ackermannweg 4, 55128, Mainz, Germany. j.koenig@imb-mainz.de.
  • 8 Institute of Molecular Biology (IMB), Ackermannweg 4, 55128, Mainz, Germany. p.beli@imb-mainz.de.

摘要


BACKGROUND:Cells have evolved quality control mechanisms to ensure protein homeostasis by detecting and degrading aberrant mRNAs and proteins. A common source of aberrant mRNAs is premature polyadenylation, which can result in non-functional protein products. Translating ribosomes that encounter poly(A) sequences are terminally stalled, followed by ribosome recycling and decay of the truncated nascent polypeptide via ribosome-associated quality control. RESULTS:Here, we demonstrate that the conserved RNA-binding E3 ubiquitin ligase Makorin Ring Finger Protein 1 (MKRN1) promotes ribosome stalling at poly(A) sequences during ribosome-associated quality control. We show that MKRN1 directly binds to the cytoplasmic poly(A)-binding protein (PABPC1) and associates with polysomes. MKRN1 is positioned upstream of poly(A) tails in mRNAs in a PABPC1-dependent manner. Ubiquitin remnant profiling and in vitro ubiquitylation assays uncover PABPC1 and ribosomal protein RPS10 as direct ubiquitylation substrates of MKRN1. CONCLUSIONS:We propose that MKRN1 mediates the recognition of poly(A) tails to prevent the production of erroneous proteins from prematurely polyadenylated transcripts, thereby maintaining proteome integrity.

KEYWORDS: MKRN1, Poly(A), RNA binding, Ribosome-associated quality control, Translation, Ubiquitin remnant profiling, Ubiquitylation, iCLIP