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A reversible form of lysine acetylation in the ER and Golgi lumen controls the molecular stabilization of BACE1

Costantini, Claudio, Ko, Mi Hee, Jonas, Mary Cabell, Puglielli, Luigi·2007·Biochemical Journal
DOI 10.1042/bj20070040
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Abstract

The lipid second messenger ceramide regulates the rate of β cleavage of the Alzheimer's disease APP (amyloid precursor protein) by affecting the molecular stability of the β secretase BACE1 (β-site APP cleaving enzyme 1). Such an event is stimulated in the brain by the normal process of aging, and is under the control of the general aging programme mediated by the insulin-like growth factor 1 receptor. In the present study we report that BACE1 is acetylated on seven lysine residues of the N-terminal portion of the nascent protein. This process involves lysine acetylation in the lumen of the ER (endoplasmic reticulum) and is followed by deacetylation in the lumen of the Golgi apparatus, once the protein is fully mature. We also show that specific enzymatic activities acetylate (in the ER) and deacetylate (in the Golgi apparatus) the lysine residues. This process requires carrier-mediated translocation of acetyl-CoA into the ER lumen and is stimulated by ceramide. Site-directed mutagenesis indicates that lysine acetylation is necessary for nascent BACE1 to leave the ER and move ahead in the secretory pathway, and for the molecular stabilization of the protein.

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  • Substitution of the seven lysine residues of BACE1 with alanine or arginine generates loss-of-acetylation mutants that are unable to reach the Golgi apparatus and are rapidly degraded in a post-ER compartment without apparent requirement of the proteasome.

    “We also showed that substitution of these residues with either alanine or arginine generated 'loss-ofacetylation' mutants that were not able to reach the Golgi apparatus.As a consequence, they were rapidly degraded in a 'post-ER' compartment without the apparent requirement of the proteasome (Costantini et al, 2007).”

    From PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1 (2008) · cites this paper as Costantini et al, 2007

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • Degradation of non-acetylated BACE1 intermediates in the post-ER compartment does not seem to involve the proteasome.

    “are degraded in a post-ER compartment through a mechanism that does not seem to involve the proteasome (Costantini et al, 2007).”

    From PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1 (2008) · cites this paper as Costantini et al, 2007

    The Results report that proteasome inhibitors did not increase levels of non-acetylated BACE1 intermediates, supporting a mechanism that does not seem to involve the proteasome. But the Results and Discussion describe these intermediates as largely retained in the ER; they do not establish degradation in a post-ER compartment. Page numbers are unavailable in our copy. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The various steady-state levels of loss-of-acetylation and gain-of-acetylation BACE1 mutants are not caused by differences in the efficiency of transcription or translation.

    “Finally, we also showed that the various steady-state levels of loss-of-acetylation and gain-ofacetylation mutants (Fig 2A) were not caused by differences in the efficiency of transcription or translation (Costantini et al, 2007).”

    From PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1 (2008) · cites this paper as Costantini et al, 2007

  • Nascent BACE1 is deacetylated in the lumen of the Golgi apparatus when the protein has achieved conformational maturation.

    “then deacetylated in the lumen of the Golgi apparatus when the protein has achieved conformational maturation.”

    From PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1 (2008) · cites this paper as Costantini et al, 2007

  • Acetylated intermediates of nascent BACE1 are able to reach the Golgi apparatus.

    “The acetylated intermediates of the nascent protein are able to reach the Golgi apparatus, whereas the non-acetylated ones are retained and degraded in a post-ER compartment.”

    From PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1 (2008) · cites this paper as Costantini et al, 2007

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Metadata

Authors
Costantini, C., Ko, M. H., Jonas, M. C., & Puglielli, L.
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2007-10-12
Volume
407
Issue
3
Pages
383-395
ISSN
  • 0264-6021
  • 1470-8728
DOI
10.1042/bj20070040
Cited by
99
References
5
Language
en

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