Inhibition of store-operated calcium entry by sub-lethal levels of proteasome inhibition is associated with STIM1/STIM2 degradation.

Abstract

Dysfunction of the ubiquitin-proteasome system (UPS) and calcium homeostasis has been implicated in the neurodegeneration of Alzheimer's and Parkinson's diseases. The cytosolic calcium concentration is maintained by store-operated calcium entry (SOCE), which is repressed by Alzheimer's disease-associated mutants, such as mutant presenilins. We hypothesized that inhibition of UPS impacts SOCE. This study showed that pretreatment with sub-lethal levels of proteasome inhibitors, including MG-132 and clasto-lactacystin-β-lactone (LA), reduced SOCE after depletion of endoplasmic reticulum calcium in rat neurons. With the same treatment, MG-132 and LA reduced the protein levels of stromal interaction molecule 1and 2 (STIM1/2), but not the levels of Orai1 and canonical transient receptor potential channel 1 (TRPC1). STIM1 or STIM2 protein was mobilized to lysosome by MG-132/LA treatment as observed under an immunofluorescence confocal laser microscope. In the neurons, MG-132 and LA degraded p62/SQSTM1, promoted autophagy, converted LC3I to LC3II, and promoted co-localization of LC3 and lysosomes. Rapamycin, which enhances autophagy, reduced STIM1/2 protein levels, whereas bafilomycin, which inhibits autophagy, increased their protein levels. The protein levels of STIM1/2 and the amplitude of SOCE were decreased in SH-SY5Y with decreased protein level of proteasome subunit beta type-5 induced by shRNA. We conclude that sub-lethal levels of proteasome inhibition reduce SOCE and promote autophagy-mediated degradation of STIM1/2. UPS inhibition, a common finding in neurodegenerative diseases, interferes with calcium homeostasis via repression of SOCE.

• Authors: Xiu-Li Kuang, Yimei Liu, Yuhua Chang, Jing Zhou, He Zhang, Yiping Li, Jia Qu, Shengzhou Wu
• Journal: Cell calcium (Cell Calcium) Vol. 59 Issue 4 Pg. 172-80 (04 2016) ISSN: 1532-1991 [Electronic] Netherlands
• PMID: 26960935 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Calcium Channels
• Membrane Glycoproteins
• Membrane Proteins
• STIM2 protein, rat
• Stim1 protein, rat
• Stromal Interaction Molecule 1
• Stromal Interaction Molecule 2
• Proteasome Endopeptidase Complex
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Calcium Channels (metabolism)
• Endoplasmic Reticulum (metabolism)
• Ion Transport (physiology)
• Membrane Glycoproteins (metabolism)
• Membrane Proteins (metabolism)
• Neurons (metabolism)
• Proteasome Endopeptidase Complex (adverse effects, metabolism)
• Rats, Sprague-Dawley
• Stromal Interaction Molecule 1 (metabolism)
• Stromal Interaction Molecule 2 (metabolism)