bims-unfpre 2023-09-03 papers

Issue of 2023‒09‒03
four papers selected by
Susan Logue, University of Manitoba

JCI Insight. 2023 Aug 31. pii: e170148. [Epub ahead of print]

The unfolded protein response links ER stress to cancer-associated thrombosis.

Oluwatoyosi Muse, Rushad Patell, Christian G Peters, Moua Yang, Emale El-Darzi, Sol Schulman, Anna Falanga, Marina Marchetti, Laura Russo, Jeffrey I Zwicker, Robert Flaumenhaft.

Thrombosis is a common complication of advanced cancer. Yet the cellular mechanisms linking malignancy to thrombosis are poorly understood. The unfolded protein response (UPR) is an ER stress response associated with advanced cancers. A proteomic evaluation of plasmas from gastric and non-small cell lung cancer patients who were monitored prospectively for venous thromboembolism demonstrated increased levels of UPR-related markers in plasmas of patients who developed clots compared to those who did not. Release of procoagulant activity into supernatants of gastric, lung, and pancreatic cancer cells was enhanced by UPR induction and blocked by antagonists of the UPR receptors IRE1α or PERK. Release of extracellular vesicles bearing tissue factor (EVTF) from pancreatic cancer cells was inhibited by siRNA-mediated knockdown of IRE1α/XBP1 or PERK pathways. Induction of UPR did not increase TF synthesis, but rather stimulated localization of TF to the cell surface. UPR-induced TF delivery to EVTFs was inhibited by Arf1 knockdown or GBF1 antagonism, confirming the role of vesicular trafficking. Our findings show that UPR activation results in increased vesicular trafficking leading to release of prothrombotic EVTFs, thus providing a mechanistic link between ER stress and cancer-associated thrombosis.

Keywords: Cancer; Hematology; Thrombosis

DOI: https://doi.org/10.1172/jci.insight.170148

EMBO J. 2023 Aug 30. e113118

ER stress induces caspase-2-tBID-GSDME-dependent cell death in neurons lytically infected with herpes simplex virus type 2.

Fanghui Ren, Ryo Narita, Ahmad S Rashidi, Stefanie Fruhwürth, Zongliang Gao, Rasmus O Bak, Martin K Thomsen, Georges Mgm Verjans, Line S Reinert, Søren R Paludan.

Neurotropic viruses, including herpes simplex virus (HSV) types 1 and 2, have the capacity to infect neurons and can cause severe diseases. This is associated with neuronal cell death, which may contribute to morbidity or even mortality if the infection is not controlled. However, the mechanistic details of HSV-induced neuronal cell death remain enigmatic. Here, we report that lytic HSV-2 infection of human neuron-like SH-SY5Y cells and primary human and murine brain cells leads to cell death mediated by gasdermin E (GSDME). HSV-2-induced GSDME-mediated cell death occurs downstream of replication-induced endoplasmic reticulum stress driven by inositol-requiring kinase 1α (IRE1α), leading to activation of caspase-2, cleavage of the pro-apoptotic protein BH3-interacting domain death agonist (BID), and mitochondria-dependent activation of caspase-3. Finally, necrotic neurons released alarmins, which activated inflammatory responses in human iPSC-derived microglia. In conclusion, lytic HSV infection in neurons activates an ER stress-driven pathway to execute GSDME-mediated cell death and promote inflammation.

Keywords: Herpes simplex virus; IRE1α; neurons; organelle stress; pyroptosis

DOI: https://doi.org/10.15252/embj.2022113118

RNA. 2023 Aug 30. pii: rna.079732.123. [Epub ahead of print]

Thioredoxin regulates the redox state and the activity of the human tRNA ligase complex.

Dhaarsini Jaksch, Johanna Irnstorfer, Petra-Franziska Kalman, Javier Martinez.

The mammalian tRNA ligase complex (tRNA-LC) catalyzes the splicing of intron-containing pre-tRNAs in the nucleus and the splicing of XBP1 mRNA during the unfolded protein response (UPR) in the cytoplasm. We recently reported that the tRNA-LC co-evolved with PYROXD1, an essential oxidoreductase that protects the catalytic cysteine of RTCB, the catalytic subunit of the tRNA-LC, against aerobic oxidation. In this study we show that the oxidoreductase Thioredoxin (TRX) preserves the enzymatic activity of RTCB under otherwise inhibiting concentrations of oxidants. TRX physically interacts with oxidized RTCB, and reduces and re-activates RTCB through the action of its redox-active cysteine pair. We further show that TRX interacts with RTCB at late stages of UPR. Since the interaction requires oxidative conditions, our findings suggest that prolonged UPR generates reactive oxygen species. Thus, our results support a functional role for TRX in securing and repairing the active site of the tRNA-LC, thereby allowing pre-tRNA splicing and UPR to occur when cells encounter mild, but still inhibitory levels of reactive oxygen species.

DOI: https://doi.org/10.1261/rna.079732.123

PLoS One. 2023 ;18(8): e0287724

Establishment of an endoplasmic reticulum stress-associated lncRNAs model to predict prognosis and immunological characteristics in hepatocellular carcinoma.

Xingyuan Shen, Siyuan Wu, Zhen Yang, Chunfu Zhu.

BACKGROUND: The endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) pathways play an essential role in the pathophysiology of hepatocellular carcinoma (HCC), and activation of the UPR pathway is strongly associated with tumor growth. However, the function of ERS-associated long non-coding RNAs (lncRNAs) in HCC is less recognized.METHODS: We have used TCGA (The Cancer Genome Atlas) to obtain clinical and transcriptome data for HCC patients and the GSEA (Gene Set Enrichment Analysis) molecular signature database to get the ERS gene. ERS-associated prognostic lncRNA was determined using univariate Cox regression study. Then, least absolute shrinkage and selection operator and multivariate Cox regression study were used to construct ERS-associated lncRNAs risk model. Next, we use Kaplan-Meier (KM) survival study, time-dependent receiver operating characteristic (ROC) curve, univariate and multivariate Cox regression study to validate and evaluate the risk model. GSEA reveals the underlying molecular mechanism of the risk model. In addition, differences in Immune cell Infiltration Study, half-maximal inhibitory concentration (IC50) and immune checkpoints blockade (ICB) treatment between high and low risk groups were analyzed.
RESULTS: We constructed a risk model consisting of 6 ERS-associated lncRNAS (containingMKLN1-AS, LINC01224, AL590705.3, AC008622.2, AC145207.5, and AC026412.3). The KM survival study showed that the prognosis of HCC patients in low-risk group was better than that in high-risk group. ROC study, univariate and multivariate Cox regression study showed that the risk model had good predictive power for HCC patients. Our verification sample verified the aforesaid findings. GSEA suggests that several tumor- and metabolism-related signaling pathways are associated with risk groups. Simultaneously, we discovered that the risk models may help in the treatment of ICB and the selection of chemotherapeutic drugs.
CONCLUSIONS: In this article, we created an ERS-associated lncRNAs risk model to help prognostic diagnosis and personalized therapy in HCC.

DOI: https://doi.org/10.1371/journal.pone.0287724