Inhibition of Nonsense-Mediated RNA Decay Activates Autophagy
Open accessAbstract
Nonsense-mediated RNA decay (NMD) is an mRNA surveillance mechanism which rapidly degrades select cytoplasmic mRNAs. We and others have shown that NMD is a dynamically regulated process inhibited by amino acid deprivation, hypoxia, and other cellular stresses commonly generated by the tumor microenvironment. This inhibition of NMD can result in the accumulation of misfolded, mutated, and aggregated proteins, but how cells adapt to these aberrant proteins is unknown. Here we demonstrate that the inhibition of NMD activates autophagy, an established protein surveillance mechanism, both in vitro and in vivo. Conversely, the hyperactivation of NMD blunts the induction of autophagy in response to a variety of cellular stresses. The regulation of autophagy by NMD is due, in part, to stabilization of the documented NMD target ATF4. NMD inhibition increases intracellular amino acids, a hallmark of autophagy, and the concomitant inhibition of autophagy and NMD, either molecularly or pharmacologically, leads to synergistic cell death. Together these studies indicate that autophagy is an adaptive response to NMD inhibition and uncover a novel relationship between an mRNA surveillance system and a protein surveillance system, with important implications for the treatment of cancer.
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MTOR-independent methods for stimulating autophagy include direct stimulation of AKT and BECN1, activating MAPK8/JNK1 to dissociate BCL2 from BECN1, applying Tat-Beclin 1, SIRT1-associated starvation, and disrupting nonsense-mediated RNA decay.
“The array of MTOR-independent methods for stimulating autophagy also includes direct stimulation of AKT and BECN1, activating MAPK8/JNK1 to dissociate BCL2 from (and thereby disinhibit) BECN1, applying the synthetic peptide Tat-Beclin 1, SIRT1-associated starvation, and disrupting nonsense-mediated RNA decay [513–517] (Figure 3).”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [517]
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Autophagy and ALS: mechanistic insights and therapeutic implications
Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J. (2022) · Autophagy · doi:10.1080/15548627.2021.1926656 · Cited by 189 · see citing works
- Authors
- Wengrod, J., Martin, L., Wang, D., Frischmeyer-Guerrerio, P., Dietz, H. C., & Gardner, L. B.
- Affiliations
- New York University (US)
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Howard Hughes Medical Institute (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2013-06-01
- Volume
- 33
- Issue
- 11
- Pages
- 2128-2135
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC3648072
- OpenAlex
- W2122840122
- Cited by
- 63
- References
- 28
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 3 · 2023: 3 · 2021: 6 · 2020: 4 · 2019: 5 · 2018: 3 · 2017: 8 · 2016: 7 · 2015: 8 · 2014: 4 · 2013: 1
- FWCI
- 4.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- NYU Langone Medical Center
- Johns Hopkins University
- York University
- National Institute of General Medical Sciences (T32GM066704)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK081641)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- nonsense-mediated mRNA decay, autophagy, mRNA surveillance, amino acid starvation, protein aggregation, cellular stress response, tumor microenvironment, synergistic cell death, cancer therapy
- MeSH terms
- Amino Acids, Animals, Autophagy, Chloroquine, HeLa Cells, Humans, Microtubule-Associated Proteins, Transcription Factors, Trans-Activators, RNA-Binding Proteins, Cell Death, RNA Helicases, RNA, Small Interfering, Green Fluorescent Proteins, Mice, Activating Transcription Factor 4, Nonsense Mediated mRNA Decay
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