Organizing Principles of Mammalian Nonsense-Mediated mRNA Decay

Popp, Maximilian W.; Maquat, Lynne

doi:10.1146/annurev-genet-111212-133424

Cited by 352 publications

(333 citation statements)

References 208 publications

(251 reference statements)

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“…Conflicting data suggest that TDP43 autoregulation involves nonsense-mediated decay (NMD) (16) or exosome-mediated degradation (15). Excess TDP43 enhances splicing in the TARDBP 3′UTR, potentially targeting the transcript for NMD, whereas deficiencies in human up-frameshift protein 1 (hUPF1), an essential component of NMD (17), result in elevated TARDBP mRNA levels (16). As with TDP43, FUS also binds to its own premRNA (14), reducing exon 7 inclusion and shifting the translational reading frame so that a premature termination codon appears in exon 8 (18).…”

mentioning

confidence: 99%

Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1

Barmada

Arjun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

114

164

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Over 30% of patients with amyotrophic lateral sclerosis (ALS) exhibit cognitive deficits indicative of frontotemporal dementia (FTD), suggesting a common pathogenesis for both diseases. Consistent with this hypothesis, neuronal and glial inclusions rich in TDP43, an essential RNA-binding protein, are found in the majority of those with ALS and FTD, and mutations in TDP43 and a related RNAbinding protein, FUS, cause familial ALS and FTD. TDP43 and FUS affect the splicing of thousands of transcripts, in some cases triggering nonsense-mediated mRNA decay (NMD), a highly conserved RNA degradation pathway. Here, we take advantage of a faithful primary neuronal model of ALS and FTD to investigate and characterize the role of human up-frameshift protein 1 (hUPF1), an RNA helicase and master regulator of NMD, in these disorders. We show that hUPF1 significantly protects mammalian neurons from both TDP43-and FUS-related toxicity. Expression of hUPF2, another essential component of NMD, also improves survival, whereas inhibiting NMD prevents rescue by hUPF1, suggesting that hUPF1 acts through NMD to enhance survival. These studies emphasize the importance of RNA metabolism in ALS and FTD, and identify a uniquely effective therapeutic strategy for these disorders.A myotrophic lateral sclerosis (ALS) is a progressive and lethal motor neuron disease that most often arises sporadically, but can be inherited in 10-15% of patients (1). Many of the genes implicated in familial ALS (fALS) encode RNA-binding proteins, including fused in sarcoma (FUS), transactive response element DNA/RNA-binding protein of 43 kDa (TDP43), and heteronuclear ribonuclear proteins (hnRNPs) (2), emphasizing RNA-based toxicity as a fundamental mechanism contributing to motor neuron degeneration in ALS.More than 40 different mutations in the TDP43 gene (TARDBP) have now been associated with fALS (3). Disease-associated mutations in TARDBP affect the turnover (4), amount (5), and subcellular localization of TDP43 (6, 7), in many cases resulting in cytoplasmic TDP43 inclusions. Affected neurons in sporadic ALS (sALS) exhibit identical inclusions containing wild-type (WT) TDP43 (8), and WT TDP43 accumulation causes neurodegeneration in cellular and animal models (6, 9, 10), providing a pathogenic link between fALS and sALS. FUS mutations have also been linked to fALS (11,12). Unlike TDP43, FUS-related pathology is limited to fALS due to FUS mutations (13). FUS and TDP43 bind largely nonoverlapping RNA targets (14), leading to the unexpected conclusion that, despite their homology and involvement in fALS, TDP43 and FUS have distinct roles in RNA metabolism.TDP43 regulates its own expression through a negative feedback loop (15), but the mechanism by which it does so remains unclear. Conflicting data suggest that TDP43 autoregulation involves nonsense-mediated decay (NMD) (16) or exosome-mediated degradation (15). Excess TDP43 enhances splicing in the TARDBP 3′UTR, potentially targeting the transcript for NMD, whereas deficiencies in human up-frameshift prote...

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mentioning

confidence: 99%

Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1

Barmada

Arjun

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

114

164

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“…In addition to the ARE-mediated mRNA decay (12)(13)(14)(15)(16)(17)(18) and the mRNA surveillance pathways, such as nonsense-mediated decay (NMD) (19), nonstop decay (NSD), or no-go decay (NGD) (20), the general mRNA degradation pathway has also been linked to translation for many years. First, the inhibition of translation with antibiotics such as cycloheximide can stabilize mRNAs (6,21,22).…”

mentioning

confidence: 99%

General and MicroRNA-Mediated mRNA Degradation Occurs on Ribosome Complexes in Drosophila Cells

Antic

Wolfinger

Skucha

et al. 2015

Molecular and Cellular Biology

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The translation and degradation of mRNAs are two key steps in gene expression that are highly regulated and targeted by many factors, including microRNAs (miRNAs). While it is well established that translation and mRNA degradation are tightly coupled, it is still not entirely clear where in the cell mRNA degradation takes place. In this study, we investigated the possibility of mRNA degradation on the ribosome in Drosophila cells. Using polysome profiles and ribosome affinity purification, we could demonstrate the copurification of various deadenylation and decapping factors with ribosome complexes. Also, AGO1 and GW182, two key factors in the miRNA-mediated mRNA degradation pathway, were associated with ribosome complexes. Their copurification was dependent on intact mRNAs, suggesting the association of these factors with the mRNA rather than the ribosome itself. Furthermore, we isolated decapped mRNA degradation intermediates from ribosome complexes and performed high-throughput sequencing analysis. Interestingly, 93% of the decapped mRNA fragments (approximately 12,000) could be detected at the same relative abundance on ribosome complexes and in cell lysates. In summary, our findings strongly indicate the association of the majority of bulk mRNAs as well as mRNAs targeted by miRNAs with the ribosome during their degradation.

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“…Instead, an intronic point mutation in NZB Nlrp3 creates a novel splice acceptor site, and subsequent incorporation of a pseudoexon with a premature termination codon. The observed lowered level of NZB Nlrp3 mRNA is likely due to nonsense-mediated decay, which is elicited by a stop codon upstream of an exon-exon boundary, marked by an exon junction complex (54). However, the truncated protein also apparently lacks stability, and the normal protein is not expressed at a high enough level in NZB to provide an NLRP3 response.…”

Section: Discussionmentioning

confidence: 97%

Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice

Sester

Sagulenko

Thygesen

et al. 2015

The Journal of Immunology

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Inflammasomes are protein complexes that promote caspase activation, resulting in processing of IL-1β and cell death, in response to infection and cellular stresses. Inflammasomes have been anticipated to contribute to autoimmunity. The New Zealand Black (NZB) mouse develops anti-erythrocyte Abs and is a model of autoimmune hemolytic anemia. These mice also develop anti-nuclear Abs typical of lupus. In this article, we show that NZB macrophages have deficient inflammasome responses to a DNA virus and fungal infection. Absent in melanoma 2 (AIM2) inflammasome responses are compromised in NZB by high expression of the AIM 2 antagonist protein p202, and consequently NZB cells had low IL-1β output in response to both transfected DNA and mouse CMV infection. Surprisingly, we also found that a second inflammasome system, mediated by the NLR family, pyrin domain containing 3 (NLRP3) initiating protein, was completely lacking in NZB cells. This was due to a point mutation in an intron of the Nlrp3 gene in NZB mice, which generates a novel splice acceptor site. This leads to incorporation of a pseudoexon with a premature stop codon. The lack of full-length NLRP3 protein results in NZB being effectively null for Nlrp3, with no production of bioactive IL-1β in response to NLRP3 stimuli, including infection with Candida albicans. Thus, this autoimmune strain harbors two inflammasome deficiencies, mediated through quite distinct mechanisms. We hypothesize that the inflammasome deficiencies in NZB alter the interaction of the host with both microflora and pathogens, promoting prolonged production of cytokines that contribute to development of autoantibodies.

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Organizing Principles of Mammalian Nonsense-Mediated mRNA Decay

Cited by 352 publications

References 208 publications

Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1

Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1

General and MicroRNA-Mediated mRNA Degradation Occurs on Ribosome Complexes in Drosophila Cells

Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice

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