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Human UPF3A and UPF3B enable fault‐tolerant activation of nonsense‐mediated mRNA decay

The paralogous human proteins UPF3A and UPF3B are involved in recognizing mRNAs targeted by nonsense‐mediated mRNA decay (NMD). UPF3B has been demonstrated to support NMD, presumably by bridging an exon junction complex (EJC) to the NMD factor UPF2. The role of UPF3A has been described either as a w...

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Main Authors: Wallmeroth, Damaris (Author) , Lackmann, Jan-Wilm (Author) , Kueckelmann, Sabrina (Author) , Altmüller, Janine (Author) , Dieterich, Christoph (Author) , Böhm, Volker (Author) , Gehring, Niels H. (Author)
Format: Article (Journal)
Language:English
Published: 22 April 2022
In: The EMBO journal
Year: 2022, Volume: 41, Issue: 10, Pages: 1-23
ISSN:1460-2075
DOI:10.15252/embj.2021109191
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.15252/embj.2021109191
Verlag, kostenfrei, Volltext: https://www.embopress.org/doi/full/10.15252/embj.2021109191
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Author Notes:Damaris Wallmeroth, Jan‐Wilm Lackmann, Sabrina Kueckelmann, Janine Altmüller, Christoph Dieterich, Volker Boehm & Niels H Gehring
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Summary:The paralogous human proteins UPF3A and UPF3B are involved in recognizing mRNAs targeted by nonsense‐mediated mRNA decay (NMD). UPF3B has been demonstrated to support NMD, presumably by bridging an exon junction complex (EJC) to the NMD factor UPF2. The role of UPF3A has been described either as a weak NMD activator or an NMD inhibitor. Here, we present a comprehensive functional analysis of UPF3A and UPF3B in human cells using combinatory experimental approaches. Overexpression or knockout of UPF3A as well as knockout of UPF3B did not substantially change global NMD activity. In contrast, the co‐depletion of UPF3A and UPF3B resulted in a marked NMD inhibition and a transcriptome‐wide upregulation of NMD substrates, demonstrating a functional redundancy between both NMD factors. In rescue experiments, UPF2 or EJC binding‐deficient UPF3B largely retained NMD activity. However, combinations of different mutants, including deletion of the middle domain, showed additive or synergistic effects and therefore failed to maintain NMD. Collectively, UPF3A and UPF3B emerge as fault‐tolerant, functionally redundant NMD activators in human cells.
Item Description:Gesehen am 18.09.2024
Physical Description:Online Resource
ISSN:1460-2075
DOI:10.15252/embj.2021109191

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