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Licensed Unlicensed Requires Authentication Published by De Gruyter December 2, 2020

Lysine acetyltransferase Tip60 acetylates the APP adaptor Fe65 to increase its transcriptional activity

  • Sabine Probst , Florian Riese , Larissa Kägi , Maik Krüger , Natalie Russi , Roger M. Nitsch and Uwe Konietzko ORCID logo EMAIL logo
From the journal Biological Chemistry

Abstract

Proteolytic processing of the amyloid precursor protein (APP) releases the APP intracellular domain (AICD) from the membrane. Bound to the APP adaptor protein Fe65 and the lysine acetyltransferase (KAT) Tip60, AICD translocates to the nucleus. Here, the complex forms spherical condensates at sites of endogenous target genes, termed AFT spots (AICD-Fe65-Tip60). We show that loss of Tip60 KAT activity prevents autoacetylation, reduces binding of Fe65 and abolishes Fe65-mediated stabilization of Tip60. Autoacetylation is a prerequisite for AFT spot formation, with KAT-deficient Tip60 retained together with Fe65 in speckles. We identify lysine residues 204 and 701 of Fe65 as acetylation targets of Tip60. We do not detect acetylation of AICD. Mutation of Fe65 K204 and K701 to glutamine, mimicking acetylation-induced charge neutralization, increases the transcriptional activity of Fe65 whereas Tip60 inhibition reduces it. The lysine deacetylase (KDAC) class III Sirt1 deacetylates Fe65 and pharmacological modulation of Sirt1 activity regulates Fe65 transcriptional activity. A second acetylation/deacetylation cycle, conducted by CBP and class I/II KDACs at different lysine residues, regulates stability of Fe65. This is the first report describing a role for acetylation in the regulation of Fe65 transcriptional activity, with Tip60 being the only KAT tested that supports AFT spot formation.


Corresponding author: Uwe Konietzko, Institute for Regenerative Medicine (IREM), University of Zurich Campus Schlieren, Wagistrasse 12, CH-8952 Schlieren, Switzerland, E-mail:

Funding source: Swiss National Science Foundation

Award Identifier / Grant number: SNF 31003A_146532, SNF 31003A_166177

Acknowledgments

We thank Peter Hunziker from the Functional Genomics Center Zürich for his support with the mass spectrometry.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was supported by the Swiss National Science Foundation SNF 31003A_166177 and SNF 31003A_146532 as well as the resources of the IREM.

  3. Conflict of interest statement: The authors declare no competing or financial interests.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2020-0279).


Received: 2020-08-10
Accepted: 2020-11-18
Published Online: 2020-12-02
Published in Print: 2021-03-26

© 2020 Walter de Gruyter GmbH, Berlin/Boston

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