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Acetylation of RTN-1C regulates the induction of ER stress by the inhibition of HDAC activity in neuroectodermal tumors

Oncogene volume 28, pages 3814–3824 (2009)Cite this article

Abstract

Reticulons are a family of highly conserved proteins, localized in the endoplasmic reticulum (ER) and involved in different cellular functions, such as intracellular membrane trafficking, apoptosis and nuclear envelope formation. The reticulon protein family consists of four members, but their specific functions are presently poorly understood. RTN-1C overexpression triggers apoptosis, regulating ER stress versus DNA damage-induced cell death in a mutually exclusive way. The different RTN isoforms share a C-terminal reticulon homology domain containing two hydrophobic segments and a 66-amino acid hydrophilic loop. In the C-terminal region of RTN-1C, a unique consensus sequence (GAKRH) has recently been identified, showing 100% identity with the DNA-binding domain of histone H4. In this study, we show that this sequence is essential for RTN-1C-mediated apoptosis. It is noteworthy that the lysine 204 present in this region is post-translationally modified by acetylation and that this event is associated with a significant decrease in histone deacetylase activity and contributes to RTN-1C binding to DNA. These data demonstrate a molecular mechanism by which RTN-1C controls apoptosis and indicate this protein to be a novel potential target for cancer therapy.

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Abbreviations

FBS:

fetal bovine serum

RTN-1C:

reticulon protein-1C

ER:

endoplasmic reticulum

HDAC:

histone deacetylase

HAT:

histone acetylase

TSA:

trichostatin A

AA:

anacardic acid

UPR:

unfolded protein responce

CRT:

calreticulin

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Acknowledgements

This work was partially supported by grants from Ricerca Corrente and Finalizzata from Ministero della Salute, AIRC, Telethon Foundation, EU integrated project ‘Apo-sys’ and Cofin 2006 to MP, and from COFIN and FIRB to CB.

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Authors and Affiliations

  1. Department of Biology, University of Rome ‘Tor Vergata’, Rome, Italy

    B Fazi, S De Rubeis, M Piacentini & F Di Sano

  2. Department of Science and Chemical Technologies, University of Rome ‘Tor Vergata’, Rome, Italy

    S Melino & M Paci

  3. Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

    S De Rubeis & C Bagni

  4. Department of Molecular and Developmental Genetics, Flanders Institute for Biotechnology (VIB), Leuven, Belgium

    S De Rubeis & C Bagni

  5. Department of Experimental Medicine and Biochemical Sciences, University of Rome ‘Tor Vergata’, Rome, Italy

    C Bagni

  6. National Institute for Infectious Diseases IRCCS ‘L Spallanzani’, Rome, Italy

    M Piacentini

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  1. B Fazi
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  2. S Melino
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  3. S De Rubeis
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  4. C Bagni
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Corresponding author

Correspondence to M Piacentini.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Fazi, B., Melino, S., De Rubeis, S. et al. Acetylation of RTN-1C regulates the induction of ER stress by the inhibition of HDAC activity in neuroectodermal tumors. Oncogene 28, 3814–3824 (2009). https://doi.org/10.1038/onc.2009.233

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