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BACKGROUND: Insomnia is a prevalent health concern in the general population associated with a range of adverse health effects. New, effective, safe and low-cost treatments, suitable for long-term use, are urgently required. Previous studies have shown the potential of electrical vestibular nerve stimulation (VeNS) in improving insomnia symptoms, however only one sham-controlled trial has been conducted on people with chronic insomnia. OBJECTIVES: /Hypothesis: Repeated VeNS delivered by the Modius Sleep device prior to sleep onset will show superior improvement in Insomnia Severity Index (ISI) scores over a 4-week period compared to sham stimulation. METHODS: In this double-blinded, multi-site, randomised, sham-controlled study, 147 participants with moderate to severe insomnia (ISI≥15) were recruited and allocated a VeNS or a sham device (1:1 ratio) which they were asked to use at home for 30 min daily (minimum 5 days per week) for 4 weeks. RESULTS: After 4 weeks, mean ISI score reduction was 2.26 greater in the VeNS treatment group than the sham group (p = 0.002). In the per protocol analysis, the treatment group had a mean ISI score decrease of 5.8 (95 % CI [-6.8, -4.81], approaching the clinically meaningful threshold of a 6-point reduction, with over half achieving a clinically significant decrease. Furthermore, the treatment group showed superior improvement to the sham group in the SF-36 (Quality of Life) energy/fatigue component (PP p = 0.004, effect size 0.26; ITT p = 0.006, effect size 0.22). CONCLUSIONS: Modius sleep has the potential to provide a viable, non-invasive and safe clinically meaningful alternative treatment option for insomnia.
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The Unfolded Protein Response (UPR) is an essential cellular process activated by the accumulation of unfolded proteins within the Endoplasmic Reticulum (ER), a condition referred to as ER stress. Three ER anchored receptors, IRE1, PERK and ATF6 act as ER stress sensors monitoring the health of the ER. Upon detection of ER stress, IRE1, PERK and ATF6 initiate downstream signaling pathways collectively referred to as the UPR. The overarching aim of the UPR is to restore ER homeostasis by reducing ER stress, however if that is not possible, the UPR transitions from a pro-survival to a pro-death response. While our understanding of the key signaling pathways central to the UPR is well defined, the same is not true of the subtle signaling events that help fine tune the UPR, supporting its ability to adapt to varying amplitudes or durations of ER stress. In this study, we demonstrate cross talk between the IRE1 and PERK branches of the UPR, wherein IRE1 via XBP1s signaling helps to sustain PERK expression during prolonged ER stress. Our findings suggest cross talk between UPR branches aids adaptiveness thereby helping to support the plasticity of UPR signaling responses.
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Proteínas Serina-Treonina Quinasas , eIF-2 Quinasa , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Transducción de Señal , Respuesta de Proteína DesplegadaRESUMEN
Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.
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The ubiquitin proteasome system (UPS) utilizes an orchestrated enzymatic cascade of E1, E2, and E3 ligases to add single or multiple ubiquitin-like molecules as post-translational modification (PTM) to proteins. Ubiquitination can alter protein functions and/or mark ubiquitinated proteins for proteasomal degradation but deubiquitinases (DUBs) can reverse protein ubiquitination. While the importance of DUBs as regulatory factors in the UPS is undisputed, many questions remain on DUB selectivity for protein targeting, their mechanism of action, and the impact of DUBs on the regulation of diverse biological processes. Furthermore, little is known about the expression and role of DUBs in tumors of the human central nervous system (CNS). In this comprehensive review, we have used publicly available transcriptional datasets to determine the gene expression profiles of 99 deubiquitinases (DUBs) from five major DUB families in seven primary pediatric and adult CNS tumor entities. Our analysis identified selected DUBs as potential new functional players and biomarkers with prognostic value in specific subtypes of primary CNS tumors. Collectively, our analysis highlights an emerging role for DUBs in regulating CNS tumor cell biology and offers a rationale for future therapeutic targeting of DUBs in CNS tumors.
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Proteínas , Ubiquitina , Humanos , Niño , Ubiquitinación , Ubiquitina/metabolismo , Proteínas/metabolismo , Proteasas Ubiquitina-Específicas/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Sistema Nervioso Central/metabolismoRESUMEN
Oxidative stress is caused by an imbalance in cellular redox state due to the accumulation of reactive oxygen species (ROS). While homeostatic levels of ROS are important for cell physiology and signaling, excess ROS can induce a variety of negative effects ranging from damage to biological macromolecules to cell death. Additionally, oxidative stress can disrupt the function of redox-sensitive organelles including the mitochondria and endoplasmic reticulum (ER). In the case of the ER, the accumulation of misfolded proteins can arise due to oxidative stress, leading to the onset of ER stress. To combat ER stress, cells initiate a highly conserved stress response called the unfolded protein response (UPR). While UPR signaling, within the context of resolving ER stress, is well characterised, how UPR mediators respond to and influence oxidative stress is less defined. In this review, we evaluate the interplay between oxidative stress, ER stress and UPR signaling networks. Specifically, we assess how UPR signaling mediators can influence antioxidant responses.
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Logue, Gorman, and Samali highlight a study by Guttman and colleagues (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202111068) that shows exogenous antigen peptides imported into the ER can activate the ER stress sensor IRE1α, attenuating cross-presentation by dendritic cells.
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Presentación de Antígeno , Endorribonucleasas , Neoplasias , Proteínas Serina-Treonina Quinasas , Células Dendríticas/inmunología , Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Endorribonucleasas/genética , Humanos , Neoplasias/inmunología , Péptidos , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
BACKGROUND: We investigated the predictive value of 11 serum biomarkers for renal and mortality end points in people with CKD. METHODS: Adults with CKD (n=139) were enrolled from outpatient clinics between February 2014 and November 2016. Biomarker quantification was performed using two multiplex arrays on a clinical-grade analyzer. Relationships between biomarkers and renal and mortality end points were investigated by random forests and Cox proportional hazards regression. RESULTS: The cohort was 56% male. The mean age was 63 years and median (IQR) CKD-EPI eGFR was 33 (24-51) ml/min per BSA. A total of 56 (40%) people developed a composite end point defined as ≥40% decline in eGFR, doubling of serum creatinine, RRT, or death over median (IQR) follow-up of 5.4 (4.7-5.7) years. Prediction of the composite end point was better with random forests trained on serum biomarkers compared with clinical variables (area under the curve of 0.81 versus 0.78). The predictive performance of biomarkers was further enhanced when considered alongside clinical variables (area under the curve of 0.83 versus 0.81 for biomarkers alone). Patients (n=27, 19%) with high soluble TNF receptor-1 (≥3 ng/ml) and neutrophil gelatinase-associated lipocalin (≥156 ng/ml), coupled with low complement 3a des-arginine (<2368 ng/ml), almost universally (96%) developed the composite renal and mortality end point. C-reactive protein (adjusted hazard ratio, 1.4; 95% CI, 1.1 to 1.8), neutrophil gelatinase-associated lipocalin (adjusted hazard ratio, 2.8; 95% CI, 1.3 to 6.1) and complement 3a desarginine (adjusted hazard ratio, 0.6; 95% CI, 0.4 to 0.96) independently predicted time to the composite end point. CONCLUSIONS: Outpatients with the triad of high soluble TNF receptor-1 and neutrophil gelatinase-associated lipocalin coupled with low complement 3a des-arginine had high adverse event rates over 5-year follow-up. Incorporation of serum biomarkers alongside clinical variables improved prediction of CKD progression and mortality. Our findings require confirmation in larger, more diverse patient cohorts.
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Insuficiencia Renal Crónica , Adulto , Biomarcadores , Creatinina , Progresión de la Enfermedad , Femenino , Humanos , Riñón , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/diagnósticoRESUMEN
Stress-induced apoptosis is mediated primarily through the intrinsic pathway that involves caspase-9. We previously reported that in caspase-9-deficient cells, a protein complex containing ATG5 and Fas-associated death domain (FADD) facilitated caspase-8 activation and cell death in response to endoplasmic reticulum (ER) stress. Here, we investigated whether this complex could be activated by other forms of cell stress. We show that diverse stress stimuli, including etoposide, brefeldin A and paclitaxel, as well as heat stress and gamma-irradiation, caused formation of a complex containing ATG5-ATG12, FADD and caspase-8 leading to activation of downstream caspases in caspase-9-deficient cells. We termed this complex the 'stressosome'. However, in these cells, only ER stress and heat shock led to stressosome-dependent cell death. Using in silico molecular modelling, we propose the structure of the stressosome complex, with FADD acting as an adaptor protein, interacting with pro-caspase-8 through their respective death effector domains (DEDs) and interacting with ATG5-ATG12 through its death domain (DD). This suggests that the complex could be regulated by cellular FADD-like interleukin-1ß-converting enzyme-inhibitory protein (cFLIPL ), which was confirmed experimentally. This study provides strong evidence for an alternative mechanism of caspase-8 activation involving the stressosome complex.
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Proteína 5 Relacionada con la Autofagia/metabolismo , Caspasa 8/metabolismo , Caspasa 9/metabolismo , Estrés del Retículo Endoplásmico , Animales , Fibroblastos , Células HEK293 , Humanos , Ratones , Células Madre Embrionarias de RatonesRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and one of the leading causes of cancer-associated deaths in the world. It is characterised by dismal response rates to conventional therapies. A major challenge in treatment strategies for PDAC is the presence of a dense stroma that surrounds the tumour cells, shielding them from treatment. This unique tumour microenvironment is fuelled by paracrine signalling between pancreatic cancer cells and supporting stromal cell types including the pancreatic stellate cells (PSC). While our molecular understanding of PDAC is improving, there remains a vital need to develop effective, targeted treatments. The unfolded protein response (UPR) is an elaborate signalling network that governs the cellular response to perturbed protein homeostasis in the endoplasmic reticulum (ER) lumen. There is growing evidence that the UPR is constitutively active in PDAC and may contribute to the disease progression and the acquisition of resistance to therapy. Given the importance of the tumour microenvironment and cytokine signalling in PDAC, and an emerging role for the UPR in shaping the tumour microenvironment and in the regulation of cytokines in other cancer types, this review explores the importance of the UPR in PDAC biology and its potential as a therapeutic target in this disease.
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Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma, is associated with a low 5-year survival and harsh treatment side effects, underscoring an urgent need for therapy. The unfolded protein response (UPR) is activated in response to endoplasmic reticulum (ER) stress, where three ER stress receptors, IRE1, PERK and ATF6, aim to restore cellular homeostasis. The UPR is pro-tumourigenic in many cancers. In this study, we investigate basal UPR activity in RMS. Basal activation of IRE1 and PERK was observed in RMS cell lines, which was diminished upon addition of the IRE1 RNase inhibitor, MKC8866, or PERK inhibitor, AMGEN44. UPR inhibition caused a reduction in cell viability, cell proliferation and inhibition of long-term colony formation in both subtypes of RMS. Alveolar RMS (ARMS) subtype was highly sensitive to IRE1 inhibition, whereas embryonal RMS (ERMS) subtypes responded more markedly to PERK inhibition. Further investigation revealed a robust activation of senescence upon UPR inhibition. For the first time, the UPR is implicated in RMS biology and phenotype, and inhibition of UPR signalling reduces cell growth, suggesting that the UPR may be a promising target in RMS.
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Endorribonucleasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Rabdomiosarcoma/patología , Respuesta de Proteína Desplegada/fisiología , eIF-2 Quinasa/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Humanos , Rabdomiosarcoma/metabolismoRESUMEN
Chemoresistance is a major factor driving tumour relapse and the high rates of cancer-related deaths. Understanding how cancer cells overcome chemotherapy-induced cell death is critical in promoting patient survival. One emerging mechanism of chemoresistance is the tumour cell secretome (TCS), an array of protumorigenic factors released by tumour cells. Chemotherapy exposure can also alter the composition of the TCS, known as therapy-induced TCS, and can promote tumour relapse and the formation of an immunosuppressive tumour microenvironment (TME). Here, we outline how the TCS can protect cancer cells from chemotherapy-induced cell death. We also highlight recent evidence describing how therapy-induced TCS can impact cancer stem cell (CSC) expansion and tumour-associated immune cells to enable tumour regrowth and antitumour immunity.
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Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Recurrencia Local de Neoplasia/patología , Neoplasias/tratamiento farmacológico , Microambiente Tumoral/inmunología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/inmunología , Resistencia a Antineoplásicos/inmunología , Humanos , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/prevención & control , Neoplasias/inmunología , Neoplasias/patología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/patología , Escape del Tumor/efectos de los fármacos , Escape del Tumor/inmunología , Microambiente Tumoral/efectos de los fármacosRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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The inflammasome is a multiprotein complex assembled in response to Pathogen Associated Molecular Patterns (PAMPs) and Danger Associated Molecular Patterns (DAMPs). Inflammasome activation occurs through a two-step mechanism, with the first signal facilitating priming of inflammasome components while the second signal triggers complex assembly. Once assembled, the inflammasome recruits and activates pro-caspase-1, which in turn processes pro-interleukin (IL)-18 and pro-IL-1ß into their bio-active forms. Owing to its key role in the regulation of innate immune responses, the inflammasome has emerged as a therapeutic target for the treatment of inflammatory conditions. In this study we demonstrate that IRE1α, a key component of the Unfolded Protein Response, contributes to assembly of the NLRP3 inflammasome. Blockade of IRE1α RNase signaling lowered NLRP3 inflammasome assembly, caspase-1 activation and pro-IL-1ß processing. These results underscore both the importance and potential therapeutic relevance of targeting IRE1α signaling in conditions of excessive inflammasome formation.
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Endorribonucleasas/antagonistas & inhibidores , Inflamasomas/metabolismo , Interleucina-1/metabolismo , Interleucina-1beta/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Precursores de Proteínas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Humanos , Inflamasomas/efectos de los fármacos , Lipopolisacáridos/farmacología , Nigericina/farmacología , Transducción de Señal , Células THP-1 , TransfecciónRESUMEN
Tumour cells endure both oncogenic and environmental stresses during cancer progression. Transformed cells must meet increased demands for protein and lipid production needed for rapid proliferation and must adapt to exist in an oxygen- and nutrient-deprived environment. To overcome such challenges, cancer cells exploit intrinsic adaptive mechanisms such as the unfolded protein response (UPR). The UPR is a pro-survival mechanism triggered by accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER), a condition referred to as ER stress. IRE1, PERK and ATF6 are three ER anchored transmembrane receptors. Upon induction of ER stress, they signal in a coordinated fashion to re-establish ER homoeostasis, thus aiding cell survival. Over the past decade, evidence has emerged supporting a role for the UPR in the establishment and progression of several cancers, including breast cancer, prostate cancer and glioblastoma multiforme. This review discusses our current knowledge of the UPR during oncogenesis, tumour growth, metastasis and chemoresistance.
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Carcinogénesis/metabolismo , Resistencia a Antineoplásicos/fisiología , Estrés del Retículo Endoplásmico/fisiología , Respuesta de Proteína Desplegada/fisiología , Animales , Retículo Endoplásmico/metabolismo , Humanos , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
In 2018, in the US alone, it is estimated that 268,670 people will be diagnosed with breast cancer, and that 41,400 will die from it. Since breast cancers often become resistant to therapies, and certain breast cancers lack therapeutic targets, new approaches are urgently required. A cell-stress response pathway, the unfolded protein response (UPR), has emerged as a promising target for the development of novel breast cancer treatments. This pathway is activated in response to a disturbance in endoplasmic reticulum (ER) homeostasis but has diverse physiological and disease-specific functions. In breast cancer, UPR signalling promotes a malignant phenotype and can confer tumours with resistance to widely used therapies. Here, we review several roles for UPR signalling in breast cancer, highlighting UPR-mediated therapy resistance and the potential for targeting the UPR alone or in combination with existing therapies.
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Triple-negative breast cancer (TNBC) lacks targeted therapies and has a worse prognosis than other breast cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFß2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Endorribonucleasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Línea Celular , Línea Celular Tumoral , Endorribonucleasas/antagonistas & inhibidores , Endorribonucleasas/genética , Inhibidores Enzimáticos/administración & dosificación , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Ratones Desnudos , Paclitaxel/administración & dosificación , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Interferencia de ARN , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
Receptor-interacting protein 2 (RIP2) is an essential mediator of inflammation and innate immunity, but little is known about its role outside the immune system. Recently, RIP2 has been linked to chemoresistance of triple negative breast cancer (TNBC), the most aggressive breast cancer subtype for which there is an urgent need for targeted therapies. In this study we show that high expression of RIP2 in breast tumors correlates with a worse prognosis and a higher risk of recurrence. We also demonstrate that RIP2 confers TNBC cell resistance against paclitaxel and ceramide-induced apoptosis. Overexpression of RIP2 lead to NF-κB activation, which contributed to higher expression of pro-survival proteins and cell survival. Conversely, RIP2 knockdown inhibited NF-κB signaling, reduced levels of anti-apoptotic proteins and sensitized cells to drug treatment. Together, these data show that RIP2 promotes survival of breast cancer cells through NF-κB activation and that targeting RIP2 may be therapeutically beneficial for treatment of TNBC.
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Supervivencia Celular , FN-kappa B/metabolismo , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Antineoplásicos/uso terapéutico , Ceramidas/uso terapéutico , Femenino , Humanos , Células MCF-7 , Paclitaxel/uso terapéutico , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Células Tumorales CultivadasRESUMEN
Cancer immune surveillance is essential for the inhibition of carcinogenesis. Malignantly transformed cells can be recognized by both the innate and adaptive immune systems through different mechanisms. Immune effector cells induce extrinsic cell death in the identified tumor cells by expressing death ligand cytokines of the tumor necrosis factor ligand family. However, some tumor cells can escape immune elimination and progress. Acquisition of resistance to the death ligand-induced apoptotic pathway can be obtained through cleavage of effector cell expressed death ligands into a poorly active form, mutations or silencing of the death receptors, or overexpression of decoy receptors and pro-survival proteins. Although the immune system is highly effective in the elimination of malignantly transformed cells, abnormal/dysfunctional death ligand signaling curbs its cytotoxicity. Moreover, DRs can also transmit pro-survival and pro-migratory signals. Consequently, dysfunctional death receptor-mediated apoptosis/necroptosis signaling does not only give a passive resistance against cell death but actively drives tumor cell motility, invasion, and contributes to consequent metastasis. This dual contribution of the death receptor signaling in both the early, elimination phase, and then in the late, escape phase of the tumor immunoediting process is discussed in this review. Death receptor agonists still hold potential for cancer therapy since they can execute the tumor-eliminating immune effector function even in the absence of activation of the immune system against the tumor. The opportunities and challenges of developing death receptor agonists into effective cancer therapeutics are also discussed.
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The VEGF family of pro-angiogenic factors has represented a pillar for targeted cancer therapy for more than a decade. In comparison, the field of protein homeostasis (proteostasis) focusing on the Unfolded Protein Response (UPR), an endoplasmic reticulum (ER) stress-induced signaling cascade, has just recently emerged as an attractive anti-cancer approach. Recent findings suggest that both signaling pathways are incontestably interrelated to ensure cell survival. Herein, we summarize recent findings that demonstrate how these two fundamental aspects of cancer cell survival intersect and provide genetic and pharmacological evidence of the interplay between angiogenic factors such as VEGF-A or PlGF and the individual members of the UPR such as IRE1, PERK and ATF6. We further describe how this interaction does not only affect the cancer cells, but also the surrounding microenvironmental niche that is also involved in tumor progression. Furthermore, by summarizing the recent therapeutic implications of both anti-angiogenic and proteostatic approaches, we emphasize how these novel findings could be used synergistically to improve cancer therapy.
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Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Animales , Antineoplásicos/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Progresión de la Enfermedad , Sinergismo Farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Homeostasis/efectos de los fármacos , Humanos , Terapia Molecular Dirigida , Neoplasias/irrigación sanguínea , Neoplasias/patología , Neovascularización Patológica/patología , Proteínas/metabolismo , Transducción de Señal/efectos de los fármacos , Microambiente Tumoral , Respuesta de Proteína Desplegada/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Upregulation of SESTRIN 2 (SESN2) has been reported in response to diverse cellular stresses. In this study we demonstrate SESTRIN 2 induction following endoplasmic reticulum (ER) stress. ER stress-induced increases in SESTRIN 2 expression were dependent on both PERK and IRE1/XBP1 arms of the unfolded protein response (UPR). SESTRIN 2 induction, post ER stress, was responsible for mTORC1 inactivation and contributed to autophagy induction. Conversely, knockdown of SESTRIN 2 prolonged mTORC1 signaling, repressed autophagy and increased ER stress-induced cell death. Unexpectedly, the increase in ER stress-induced cell death was not linked to autophagy inhibition. Analysis of UPR pathways identified prolonged eIF2α, ATF4 and CHOP signaling in SESTRIN 2 knockdown cells following ER stress. SESTRIN 2 regulation enables UPR derived signals to indirectly control mTORC1 activity shutting down protein translation thus preventing further exacerbation of ER stress.