Rifampicin Protects PC12 Cells from Rotenone-Induced Cytotoxicity by Activating GRP78 via PERK-eIF2α-ATF4 Pathway
Open accessAbstract
Rifampicin has been proposed as a therapeutic candidate for Parkinson's disease (PD). We previously showed that rifampicin was neuroprotective in PD models in vivo and in vitro. However, the molecular mechanisms underlying are not fully elucidated. In this study, using the comprehensive proteomic analysis, we identified that the 78 kDa glucose-regulated protein (GRP78), a hallmark of the unfolded protein response (UPR), was upregulated in rifampicin-treated PC12 cells. Western blot analysis confirmed GRP78 activation. GRP78 functions cytoprotectively in stressed cells, therefore, we hypothesized that GRP78 mediated rifampicin-induced neuroprotection. Using RNA interference, we found that GRP78 gene knockdown significantly attenuated the neuroprotective effects of rifampicin. Next, we examined three UPR transducers, namely, protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol requiring kinase α (IREα) and activating transcription factor 6 (ATF 6), and how they regulated rifampicin-stimulated GRP78 expression. Our results showed that PERK, eukaryotic initiation factor 2α (eIF2α), and activating transcription factor 4 (ATF4) were activated in rifampicin-treated PC12 cells. Silencing the ATF4 gene using RNAi inhibited GRP78 stimulation. Interestingly, we did not detect significant IREα activation, X-box binding protein 1 mRNA splicing, or ATF6 cleavage up to 24 h after rifampicin treatment. Taken together, our data suggested that rifampicin induced GRP78 via the PERK-eIF2α-ATF4 pathway to protect neurons against rotenone-induced cell damage. Targeting molecules in this pathway could be a novel therapeutic approach for PD treatment.
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Rifampicin upregulates GRP78 through the PERK/eIF2α/ATF4 pathway.
“Although not completely defined, rifampicin appears to sustain cell viability through different mechanisms: (i) by enhancing autophagy [293,295]; (ii) via PI3K/Akt/GSK-3β/CREB pathway modulation [296]; (iii) by upregulating the unfolded protein response marker GRP78 through the PERK/eIF2α/ATF4 pathway [297].”
From The Interplay between Gut Microbiota and Parkinson’s Disease: Implications on Diagnosis and Treatment (2022) · cites this paper as [297]
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Self-citation
- Authors
- Jing, X., Shi, Q., Bi, W., Zeng, Z., Liang, Y., Wu, X., Xiao, S., Liu, J., Yang, L., & Tao, E.
- Affiliations
- Sun Yat-sen University (CN)
- Stanford Medicine (US)
- Corresponding author
- Tao, Enxiang
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-03-17
- Volume
- 9
- Issue
- 3
- Pages
- e92110
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3956889
- OpenAlex
- W2014381302
- Cited by
- 38
- References
- 39
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 7 · 2018: 3 · 2017: 4 · 2015: 4 · 2014: 1
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81371391)
- Ministry of Education of the People's Republic of China (20070558257)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- rifampicin, Parkinson's disease, neuroprotection, GRP78, PERK-eIF2α-ATF4 pathway, unfolded protein response, PC12 cells, ATF6, XBP1 splicing, endoplasmic reticulum stress
- MeSH terms
- Regulatory Factor X Transcription Factors, Endoplasmic Reticulum Chaperone BiP, Animals, DNA-Binding Proteins, Endoribonucleases, Heat-Shock Proteins, Rifampin, Rotenone, Time Factors, Transcription Factors, Electrophoresis, Gel, Two-Dimensional, Signal Transduction, Eukaryotic Initiation Factor-2, PC12 Cells, Cell Death, Neuroprotective Agents, eIF-2 Kinase, Rats, Activating Transcription Factor 4, Activating Transcription Factor 6
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