Modulation of SF3B1 in the pre-mRNA spliceosome induces a RIG-I-dependent type I IFN response

Chang, Amy; Zhou, Yu; Iyengar, Sharanya; Pobiarzyn, Piotr W.; Tishchenko, P. Ya.; Shah, Kesha M.; Wheeler, Heather; Wang, Yueming; Loria, Paula M.; Loganzo, Frank; Woo, Seng-Ryong

doi:10.1016/j.jbc.2021.101277

Cited by 8 publications

(7 citation statements)

References 55 publications

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“…We next performed gene set enrichment analysis (GSEA), which revealed IFN-α-response as the most significantly enriched pathway in KPC-Sf3b1 K700E/+ tumor cells ( Figure 2—figure supplement 1C ). This result is in line with a previous study, which found that aberrant splicing caused by SF3B1 inhibition or oncogenic SF3B1 mutations induces an IFN-α-response through retinoic acid-inducible gene I (RIG-I) mediated recognition of cytosolic aberrant RNA-species ( Chang et al, 2021 ). Interestingly, epithelial-mesenchymal transition (EMT) emerged as the most significantly attenuated gene set in KPC-Sf3b1 K700E/+ cells ( Figure 2A and B , Figure 2—figure supplement 1C ).…”

Section: Resultssupporting

confidence: 93%

Mutant SF3B1 promotes malignancy in PDAC

Simmler,

Ioannidi,

Mengis

et al. 2023

eLife

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The splicing factor SF3B1 is recurrently mutated in various tumors, including pancreatic ductal adenocarcinoma (PDAC). The impact of the hotspot mutation SF3B1K700E on the PDAC pathogenesis, however, remains elusive. Here, we demonstrate that Sf3b1K700E alone is insufficient to induce malignant transformation of the murine pancreas, but that it increases aggressiveness of PDAC if it co-occurs with mutated KRAS and p53. We further show that Sf3b1K700E already plays a role during early stages of pancreatic tumor progression and reduces the expression of TGF-β1-responsive epithelial-mesenchymal transition (EMT) genes. Moreover, we found that SF3B1K700E confers resistance to TGF-β1-induced cell death in pancreatic organoids and cell lines, partly mediated through aberrant splicing of Map3k7. Overall, our findings demonstrate that SF3B1K700E acts as an oncogenic driver in PDAC, and suggest that it promotes the progression of early stage tumors by impeding the cellular response to tumor suppressive effects of TGF-β.

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Section: Resultssupporting

confidence: 93%

Mutant SF3B1 promotes malignancy in PDAC

Simmler,

Ioannidi,

Mengis

et al. 2023

eLife

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show abstract

“…2C). This result is in line with a previous study, which found that aberrant splicing caused by SF3B1 inhibition or oncogenic SF3B1 mutations induces an IFN-α-response through retinoic acid-inducible gene I (RIG-I) mediated recognition of cytosolic aberrant RNA-species (Chang et al, 2021). Interestingly, the most significantly depleted gene set in KPC-Sf3b1 K700E/+ cells was epithelial-mesenchymal transition (EMT) (Fig.…”

Section: Resultssupporting

confidence: 93%

Mutant SF3B1 promotes PDAC malignancy through TGF-β resistance

Simmler

Mengis

Van-Lehmann

et al. 2022

Preprint

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The splicing factor SF3B1 is recurrently mutated in various tumors, including pancreatic ductal adenocarcinoma (PDAC). The impact of the hotspot mutation SF3B1K700E on the PDAC pathogenesis, however, remains elusive. Here, we demonstrate that Sf3b1K700E alone is insufficient to induce malignant transformation of the murine pancreas, but increases aggressiveness of PDAC if it co-occurs together with mutated KRAS and p53. We further demonstrate that SF3B1K700E reduces epithelial–mesenchymal transition (EMT) and confers resistance to TGF-β1-induced cell death, and provide evidence that this phenotype is in part mediated through aberrant splicing of Map3k7. Taken together, our work suggests that SF3B1K700E acts as an oncogenic driver in PDAC through enhancing resistance to the tumor suppressive effects of TGF-β.

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“…The commonly shared enrichment between all three‐cell death EVs according to the low stringent analysis (ribosome biogenesis, RNA splicing, RNP complexes, RNA transport and localization, and RNA export from the nucleus) (Figure S3d ) could be a sign of rapid perturbation of spliceosome‐related processes and nuclear RNA export during any RCD type. The concealing effect of EVs may prevent nucleic acid sensing responses and temper associated inflammatory signalling against spliceosomes and associated factors (Chang et al., 2021 ). In that respect the stringent analysis revealed a bias towards the exclusive enrichment of proteins involved in ribosome biogenesis, rRNA metabolic processing, and (m)RNA catabolic processes in the case of apoEVs and necEVs but not ferEVs.…”

Section: Discussionmentioning

confidence: 99%

Systematic compositional analysis of exosomal extracellular vesicles produced by cells undergoing apoptosis, necroptosis and ferroptosis

Cappe,

Vadi,

Sack

et al. 2023

J of Extracellular Vesicle

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Formation of extracellular vesicles (EVs) has emerged as a novel paradigm in cell‐to‐cell communication in health and disease. EVs are notably produced during cell death but it had remained unclear whether different modalities of regulated cell death (RCD) influence the biogenesis and composition of EVs. To this end, we performed a comparative analysis of steady‐state (ssEVs) and cell death‐associated EVs (cdEVs) following TNF‐induced necroptosis (necEVs), anti‐Fas‐induced apoptosis (apoEVs), and ML162‐induced ferroptosis (ferEVs) using the same cell line. For each RCD condition, we determined the biophysical and biochemical characteristics of the cell death‐associated EVs (cdEVs), the protein cargo, and the presence of methylated ribosomal RNA. We found that the global protein content of all cdEVs was increased compared to steady‐state EVs. Qualitatively, the isolated exosomal ssEVs and cdEVs, contained a largely overlapping protein cargo including some quantitative differences in particular proteins. All cdEVs were enriched for proteins involved in RNA splicing and nuclear export, and showed distinctive rRNA methylation patterns compared to ssEVs. Interestingly, necEVs and apoEVs, but strikingly not ferEVs, showed enrichment of proteins involved in ribosome biogenesis. Altogether, our work documents quantitative and qualitative differences between ssEVs and cdEVs.

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Modulation of SF3B1 in the pre-mRNA spliceosome induces a RIG-I-dependent type I IFN response

Cited by 8 publications

References 55 publications

Mutant SF3B1 promotes malignancy in PDAC

Mutant SF3B1 promotes malignancy in PDAC

Mutant SF3B1 promotes PDAC malignancy through TGF-β resistance

Systematic compositional analysis of exosomal extracellular vesicles produced by cells undergoing apoptosis, necroptosis and ferroptosis

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