TRIM13 regulates caspase-8 ubiquitination, translocation to autophagosomes and activation during ER stress induced cell death

Tomar, Dhanendra; Prajapati, Paresh; Sripada, Lakshmi; Singh, Kritarth; Singh, Rochika; Singh, Arun Kumar

doi:10.1016/j.bbamcr.2013.08.021

Cited by 52 publications

(43 citation statements)

References 35 publications

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“…Alterations in TRIMs are associated with diverse pathological conditions, including developmental disorders, autoimmune disease, viral infections and cancer. A number of TRIMs, such as TRIM13, TRIM8, TRIM19 and TRIM26, function as tumor suppressor proteins by regulating transcriptional activity and apoptosis in a variety of cancer types2021222324. For instance, TRIM19, also known as Promyelocytic leukemia protein (PML), has a tumor suppressor function, and cells derived from PML −/− mice are defective in inducing apoptosis by Fas, TNFα, or interferons25.…”

Section: Discussionmentioning

confidence: 99%

TRIM14 is a Putative Tumor Suppressor and Regulator of Innate Immune Response in Non-Small Cell Lung Cancer

Hai

Zhu

Wang

et al. 2017

Sci Rep

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Non-small-cell lung carcinoma (NSCLC) accounts for 85% of malignant lung tumors and is the leading cause of cancer deaths. Our group previously identified Tripartite Motif 14 (TRIM14) as a component of a prognostic multigene expression signature for NSCLC. Little is known about the function of TRIM14 protein in normal or disease states. We investigated the functional and prognostic role of TRIM14 in NSCLC using in vitro and in vivo perturbation model systems. Firstly, a pooled RNAi screen identified TRIM14 to effect cell proliferation/survival in NSCLC cells. Secondly, silencing of TRIM14 expression significantly enhanced tumor growth in NSCLC xenograft mouse models, while exogenous TRIM14 expression attenuated tumorigenesis. In addition, differences in apoptotic activity between TRIM14-deficient and control tumors suggests that TRIM14 tumor suppressor activity may depend on cell death signaling pathways. TRIM14-deficient cell lines showed both resistance to hypoxia-induced cell death and attenuation of interferon response via STAT1 signaling. Consistent with these phenotypes, multivariate analyses on published mRNA expression datasets of over 600 primary NSCLCs demonstrated that low TRIM14 mRNA levels are significantly associated with poorer prognosis in early stage NSCLC patients. Our functional data therefore establish a novel tumor suppressive role for TRIM14 in NSCLC progression.

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Section: Discussionmentioning

confidence: 99%

TRIM14 is a Putative Tumor Suppressor and Regulator of Innate Immune Response in Non-Small Cell Lung Cancer

Hai

Zhu

Wang

et al. 2017

Sci Rep

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“…Cell death is largely associated with increased ATF4 and CHOP levels, whereby autophagy (which can also be regulated transcriptionally by ATF4 and CHOP) is recognized as a major pro-survival mechanism that counteracts excessive UPR-signaling [14]. Although most studies indicate that autophagy has a pro-survival function following ERS, a heightened degree/duration of stress can induce autophagy-dependent cell death mechanisms [15–17]. …”

Section: The Upr and Autophagymentioning

confidence: 99%

UPR, autophagy, and mitochondria crosstalk underlies the ER stress response

Senft

Ronai

2015

Trends in Biochemical Sciences

862

687

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Cellular stress, induced by external or internal cues, activates several well-orchestrated processes aimed at either restoring cellular homeostasis or committing to cell death. Those processes include the unfolded protein response (UPR), autophagy, hypoxia, and mitochondrial function, which are part of the global ER stress (ERS) response. When one of the ERS elements is impaired, as often occurs under pathological conditions, overall cellular homeostasis may be perturbed. Further, activation of the UPR could trigger changes in mitochondrial function or autophagy, which could modulate the UPR, exemplifying cross-talk processes. Among the numerous factors that control the magnitude or duration of these processes are ubiquitin ligases, which govern overall cellular stress outcomes. Here we summarize crosstalk among fundamental processes governing ERS responses.

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“…This intracellular DISC (iDISC) or stressosome has been described upon tunicamycin treatment in human colon tumor cells and in breast cancer cell lines and it results on caspase-8 dependent cell death [63]. In this model, TRIM13, a RING-E3 ubiquitin ligase, poly-ubiquitinates caspase-8 on K63 which stabilized it and is responsible for its activation during ER stress.…”

Section: Author Manuscriptmentioning

confidence: 99%

Cell death induced by endoplasmic reticulum stress

2015

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The endoplasmic reticulum (ER) is an organelle with multiple functions. The synthesis of transmembrane proteins and proteins that are to be secreted occur in this organelle. Many Author ManuscriptThis article is protected by copyright. All rights reserved conditions that impose stress to the cells, including hypoxia, starvation, infections and changes in secretory needs challenge the folding capacity of the cell and promote ER stress. The cellular response involves the activation of sensors that transduce signaling cascades with the aim to restore homeostasis. This is known as the Unfolded Protein Response (UPR), which also intersects with the Integrated Stress Response (ISR) that reduces protein synthesis through inactivation of the initiation factor eIF2α. Central to the UPR are the sensors PERK, IRE1 and ATF6, as well as other signaling nodes such as JNK and the downstream transcription factors XBP-1, ATF4 and CHOP. These proteins aim to restore homeostasis but they can also induce cell death, which has been shown to occur by necroptosis and, more commonly, through the regulation of Bcl-2 family proteins (Bim, Noxa and Puma) that leads to mitochondrial apoptosis. Additionally, ER stress and proteotoxic stress have been shown to induce TRAIL receptors and activation of Caspase-8.ER stress is a common feature in the pathology of numerous diseases as it plays a role in neurodegeneration, stroke, cancer, metabolic diseases and inflammation. Understanding how cells react to ER stress can accelerate discovery of drugs against these diseases. KeywordsEndoplasmic reticulum stress The endoplasmic reticulum and the Unfolded Protein Response sensorsThe endoplasmic reticulum (ER) is the organelle where transmembrane proteins and proteins that are going to be secreted are synthesized and folded. This organelle, however, is essential for multiple other cellular functions such as Ca 2+ buffering, biosynthesis of phospholipids and cholesterol. Synthesis of proteins, cholesterol and some metabolites is an ATP demanding process that also requires the right ionic strength. Disturbances in many homeostatic processes will thus lead to a state in which protein folding slows down (ER stress). The subsequent accumulation of misfolded or unfolded proteins will indicate problems in cellular homeostasis that frequently end up in cell death.Problems in protein folding can occur due to stressors apparently disparate such as starvation or viral infection. These stimuli promote the activation of a series of signals that promote synthesis of new proteins to cope with stress while reducing general protein synthesis [1,2]. This is called the Unfolded Protein Response (UPR). Another way by which the UPR aims to restore homeostasis is the stimulation of protein degradation via autophagy and the enhanced clearance of unfolded proteins by a process termed ER-Associated Degradation (ERAD).The UPR is orchestrated by three main sensors that reside in the membrane of the ER. These transmembrane proteins bind to the chaperone GRP78/BiP in the...

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TRIM13 regulates caspase-8 ubiquitination, translocation to autophagosomes and activation during ER stress induced cell death

Cited by 52 publications

References 35 publications

TRIM14 is a Putative Tumor Suppressor and Regulator of Innate Immune Response in Non-Small Cell Lung Cancer

TRIM14 is a Putative Tumor Suppressor and Regulator of Innate Immune Response in Non-Small Cell Lung Cancer

UPR, autophagy, and mitochondria crosstalk underlies the ER stress response

Cell death induced by endoplasmic reticulum stress

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