Inhibition of store-operated calcium entry by sub-lethal levels of proteasome inhibition is associated with STIM1/STIM2 degradation. Issue 4 (April 2016)

• Record Type: Journal Article
• Authors: Kuang, Xiu-li; Liu, Yimei; Chang, Yuhua; Zhou, Jing; Zhang, He; Li, Yiping; Qu, Jia; Wu, Shengzhou
• Is Part Of: Cell calcium. Volume 59:Issue 4(2016)
• Page Start: 172
• Page End: 180
• Publication Date: 2016-04
• Subjects: AD Alzheimer' disease -- PD Parkinson's disease -- SOCC store-operated calcium channel -- SOCE store-operated calcium entry -- UPS ubiquitin-proteasome system -- ER endoplasmic reticulum -- STIM stromal interaction molecule -- TRPC canonical transient receptor potential channel -- PSMB5 proteasome beta subunit type-5 -- MG-132 carbobenzoxy-l-leucyl-l-leucyl-l-leucinal LA -- LC3 microtubule-associated protein light chain -- P62/SQSTM1 sequestosome1 -- PS presenilin; Stromal interaction molecule -- Ubiquitin-proteasome system -- PSMB5 -- Orai1 -- Store-operated calcium channel -- Presenilin -- Low calcium -- ER stress -- Neurodegeneration; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2016.01.007
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical abstract: Highlights: Proteasome inhibition repressed SOCE. Proteasome inhibition decreased STIM1 and STIM2 protein levels. Proteasome inhibition activated autophagy. Rapamycin decreased vs. bafilomycin increased STIM1/STIM2. 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.