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Amyloid ? production is regulated by ?2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor.

ABSTRACT: Alteration of ryanodine receptor (RyR)-mediated calcium (Ca²⁺) signaling has been reported in Alzheimer disease (AD) models. However, the molecular mechanisms underlying altered RyR-mediated intracellular Ca²⁺ release in AD remain to be fully elucidated. We report here that RyR2 undergoes post-translational modifications (phosphorylation, oxidation, and nitrosylation) in SH-SY5Y neuroblastoma cells expressing the ?-amyloid precursor protein (?APP) harboring the familial double Swedish mutations (APPswe). RyR2 macromolecular complex remodeling, characterized by depletion of the regulatory protein calstabin2, resulted in increased cytosolic Ca²⁺ levels and mitochondrial oxidative stress. We also report a functional interplay between amyloid ? (A?), ?-adrenergic signaling, and altered Ca²⁺ signaling via leaky RyR2 channels. Thus, post-translational modifications of RyR occur downstream of A? through a ?2-adrenergic signaling cascade that activates PKA. RyR2 remodeling in turn enhances ?APP processing. Importantly, pharmacological stabilization of the binding of calstabin2 to RyR2 channels, which prevents Ca²⁺ leakage, or blocking the ?2-adrenergic signaling cascade reduced ?APP processing and the production of A? in APPswe-expressing SH-SY5Y cells. We conclude that targeting RyR-mediated Ca²⁺ leakage may be a therapeutic approach to treat AD.

SUBMITTER: Bussiere R

PROVIDER: S-EPMC5473221 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Amyloid β production is regulated by β2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor.

Bussiere Renaud R Lacampagne Alain A Reiken Steven S Liu Xiaoping X Scheuerman Valerie V Zalk Ran R Martin Cécile C Checler Frederic F Marks Andrew R AR Chami Mounia M

The Journal of biological chemistry 20170505 24

Alteration of ryanodine receptor (RyR)-mediated calcium (Ca<sup>2+</sup>) signaling has been reported in Alzheimer disease (AD) models. However, the molecular mechanisms underlying altered RyR-mediated intracellular Ca<sup>2+</sup> release in AD remain to be fully elucidated. We report here that RyR2 undergoes post-translational modifications (phosphorylation, oxidation, and nitrosylation) in SH-SY5Y neuroblastoma cells expressing the β-amyloid precursor protein (βAPP) harboring the familial dou ...[more]

PMID: 28476886

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Project description:The ubiquitin-proteasome system (UPS) is one of the major protein degradation pathways in eukaryotic cells. Abnormal functioning of this system has been observed in cancer and neurological diseases. The 20S proteasomes, essential components of the UPS, are present not only within the cells but also in the extracellular space, and their concentration in blood plasma has been found to be elevated and dependent upon the disease state, being of prognostic significance in patients suffering from cancer, liver diseases, and autoimmune diseases. However, functions of extracellular proteasomes and mechanisms of their release by cells remain largely unknown. The main mechanism of proteasome activity regulation is provided by modulation of their composition and post-translational modifications (PTMs). Moreover, diverse PTMs of proteins are known to participate in the loading of specific elements into extracellular vesicles. Since previous studies have revealed that the transport of extracellular proteasomes may occur via extracellular vesicles, we have set out to explore the PTMs of extracellular proteasomes in comparison to cellular counterparts. In this work, cellular and extracellular proteasomes were affinity purified and separated by SDS-PAGE for subsequent trypsinization and matrix-assisted laser desorption/ionization (MALDI) Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry (MS) analysis. In total, we could identify 64 and 55 PTM sites in extracellular and cellular proteasomes, respectively, including phosphorylation, ubiquitination, acetylation, and succinylation. We observed novel sites of acetylation at K238 and K192 of the proteasome subunits β2 and β3, respectively, that are specific for extracellular proteasomes. Moreover, cellular proteasomes show specific acetylation at K227 of α2 and ubiquitination at K201 of β3. Interestingly, succinylation of β6 at the residue K228 seems not to be present exclusively in extracellular proteasomes, whereas both extracellular and cellular proteasomes may also be acetylated at this site. The same situation takes place at K201 of the β3 subunit where ubiquitination is seemingly specific for cellular proteasomes. Moreover, crosstalk between acetylation, ubiquitination, and succinylation has been observed in the subunit α3 of both proteasome populations. These data will serve as a basis for further studies, aimed at dissection of the roles of extracellular proteasome-specific PTMs in terms of the function of these proteasomes and mechanism of their transport into extracellular space.

Dataset Information

Amyloid ? production is regulated by ?2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor.

Publications

Amyloid β production is regulated by β2-adrenergic signaling-mediated post-translational modifications of the ryanodine receptor.

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