AKIRIN2 controls the nuclear import of proteasomes in vertebrates

Melanie Almeida, Matthias Hinterndorfer, Hanna Brunner, Irina Grishkovskaya, Kashish Singh, Alexander Schleiffer, Julian Jude, Sumit Deswal, Robert Kalis, Milica Vunjak, Thomas Lendl, Richard Imre, Elisabeth Roitinger, Tobias Neumann, Susanne Kandolf, Michael Schutzbier, Karl Mechtler, Gijs A. Versteeg, David Haselbach () and Johannes Zuber ()
Additional contact information
Melanie Almeida: Vienna BioCenter (VBC)
Matthias Hinterndorfer: Vienna BioCenter (VBC)
Hanna Brunner: Vienna BioCenter (VBC)
Irina Grishkovskaya: Vienna BioCenter (VBC)
Kashish Singh: Vienna BioCenter (VBC)
Alexander Schleiffer: Vienna BioCenter (VBC)
Julian Jude: Vienna BioCenter (VBC)
Sumit Deswal: Vienna BioCenter (VBC)
Robert Kalis: Vienna BioCenter (VBC)
Milica Vunjak: Doctoral School of the University at Vienna and Medical University of Vienna, Vienna BioCenter (VBC)
Thomas Lendl: Vienna BioCenter (VBC)
Richard Imre: Vienna BioCenter (VBC)
Elisabeth Roitinger: Vienna BioCenter (VBC)
Tobias Neumann: Vienna BioCenter (VBC)
Susanne Kandolf: Vienna BioCenter (VBC)
Michael Schutzbier: Vienna BioCenter (VBC)
Karl Mechtler: Vienna BioCenter (VBC)
Gijs A. Versteeg: University of Vienna, Vienna BioCenter (VBC)
David Haselbach: Vienna BioCenter (VBC)
Johannes Zuber: Vienna BioCenter (VBC)

Nature, 2021, vol. 599, issue 7885, 491-496

Abstract: Abstract Protein expression and turnover are controlled through a complex interplay of transcriptional, post-transcriptional and post-translational mechanisms to enable spatial and temporal regulation of cellular processes. To systematically elucidate such gene regulatory networks, we developed a CRISPR screening assay based on time-controlled Cas9 mutagenesis, intracellular immunostaining and fluorescence-activated cell sorting that enables the identification of regulatory factors independent of their effects on cellular fitness. We pioneered this approach by systematically probing the regulation of the transcription factor MYC, a master regulator of cell growth1–3. Our screens uncover a highly conserved protein, AKIRIN2, that is essentially required for nuclear protein degradation. We found that AKIRIN2 forms homodimers that directly bind to fully assembled 20S proteasomes to mediate their nuclear import. During mitosis, proteasomes are excluded from condensing chromatin and re-imported into newly formed daughter nuclei in a highly dynamic, AKIRIN2-dependent process. Cells undergoing mitosis in the absence of AKIRIN2 become devoid of nuclear proteasomes, rapidly causing accumulation of MYC and other nuclear proteins. Collectively, our study reveals a dedicated pathway controlling the nuclear import of proteasomes in vertebrates and establishes a scalable approach to decipher regulators in essential cellular processes.

Date: 2021
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DOI: 10.1038/s41586-021-04035-8

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