The stress-inducible transcription factor ATF4 accumulates at specific rRNA-processing nucleolar regions after proteasome inhibition

Valentina Galimberti, Noa Kinor, Yaron Shav-Tal, Marco Biggiogera, Ansgar Brüning

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Functional protein homeostasis is essential for the maintenance of normal cellular physiology, cell growth, and cell survival. Proteasome inhibition in cancer cells can disturb protein homeostasis in such a way that synthetic proteasome inhibitors like bortezomib may selectively kill myeloma cells. Solid cancer cells appear to respond less to bortezomib which may in part be due to a rescue mechanism of the unfolded protein response/endoplasmic reticulum stress mechanism which leads to a temporary shutdown of protein biosynthesis at the translational level. Here we show that proteasome inhibition by bortezomib may also interfere with general protein biosynthesis already at the stage of nucleolar ribosome biogenesis. Ultrastructural analysis revealed not only that bortezomib induces conspicuous changes in cytoplasmic morphology but also pronounced morphological changes of the nucleolar ultrastructure, associated with an accumulation of the transcription factor ATF4 at nucleolar sites. Stress-induced intra-nucleolar ATF4 accumulation was observed in cancer cells in a dose and time dependent manner and ultrastructural studies revealed that ATF4 is preferentially localized inside the dense fibrillar and granular component of nucleoli. Furthermore, bortezomib affected not only the number of nucleoli, but also the volume and distribution of nucleolar components. The localization of ATF4 in the granular component of nucleoli together with its association with nascent RNA transcripts in cells undergoing proteotoxic cell stress could suggest a new function for ATF4 in cell stress management.

Original languageEnglish
Pages (from-to)389-400
Number of pages12
JournalEuropean Journal of Cell Biology
Issue number10
StatePublished - 1 Oct 2016

Bibliographical note

Funding Information:
We are grateful to Prof. M.T. Boyd, Dr. N. Vlatkovic and Dr. C.P. Rubbi from University of Liverpool for valuable scientific help into this study. We thank F. Flach Biggiogera for her treasured help about nucleolar spread preparation. This work was supported by Fondo di Ateneo per la Ricerca of the University of Pavia, Italy.

Publisher Copyright:
© 2016 Elsevier GmbH


  • ATF4
  • Bortezomib
  • CHOP
  • Nucleoli
  • p53
  • rRNA


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