SIRT1 Promotes Cell Survival under Stress by Deacetylation-Dependent Deactivation of Poly(ADP-Ribose) Polymerase 1

ABSTRACT Poly(ADP-ribose) polymerase 1 (PARP1) and SIRT1 deacetylase are two NAD-dependent enzymes which play major roles in the decision of a cell to live or to die in a stress situation. Because of the dependence of both enzymes on NAD, cross talk between them has been suggested. Here, we show that PARP1 is acetylated after stress of cardiomyocytes, resulting in the activation of PARP1, which is independent of DNA damage. SIRT1 physically binds to and deacetylates PARP1. Increased acetylation of PARP1 was also detected in hearts of SIRT1−/− mice, compared to that detected in the hearts of SIRT1+/+ mice, confirming a role of SIRT1 in regulating the PARP1 acetylation in vivo. SIRT1-dependent deacetylation blocks PARP1 activity, and it protects cells from PARP1-mediated cell death. We also show that SIRT1 negatively regulates the activity of the PARP1 gene promoter, thus suggesting that the deacetylase controls the PARP1 activity at the transcriptional level as well. These data demonstrate that the activity of PARP1 is under the control of SIRT1, which is necessary for survival of cells under stress conditions.

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OXPHOS Promotes Apoptotic Resistance and Persistence in TH17 cells

10.1101/2021.10.01.462812 ◽

2021 ◽

Author(s):

Hanna S. Hong ◽

Nneka E. Mbah ◽

Mengrou Shan ◽

Kristen Loesel ◽

Lin Lin ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Cell Fate ◽

Apoptotic Cell ◽

Metabolic Phenotype ◽

Tumor Studies ◽

A Cell

AbstractApoptotic cell death is a cell-intrinsic, immune tolerance mechanism that regulates the magnitude and resolution of T cell-mediated responses. Evasion of apoptosis is critical for the generation of memory T cells, as well as autoimmune T cells, and knowledge of the mechanisms that enable resistance to apoptosis will provide insight into ways to modulate their activity during protective and pathogenic responses. IL-17-producing CD4 T cells (TH17s) are long-lived, memory cells. These features enable their role in host defense, chronic inflammatory disorders, and anti-tumor immunity. A growing number of reports now indicate that TH17s in vivo require mitochondrial oxidative phosphorylation (OXPHOS), a metabolic phenotype that is poorly induced in vitro. To elucidate the role of OXPHOS in TH17 processes, we developed a system to polarize TH17s that metabolically resembled their in vivo counterparts. We discovered that directing TH17s to use OXPHOS promotes mitochondrial fitness, glutamine anaplerosis, and an anti-apoptotic phenotype marked by high BCL-XL and low BIM. Through competitive co-transfer experiments and tumor studies, we further revealed how OXPHOS protects TH17s from cell death while enhancing their persistence in the periphery and tumor microenvironment. Together, our work demonstrates a non-classical role of metabolism in regulating TH17 cell fate and highlights the potential for therapies that target OXPHOS in TH17-driven diseases.

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N-acetylaspartate improves cell survival when glucose is limiting

10.1101/2020.05.28.114629 ◽

2020 ◽

Author(s):

H. Furkan Alkan ◽

Katharina E. Walter ◽

Hubert Hackl ◽

Matthew G. Vander Heiden ◽

Tobias Madl ◽

...

Keyword(s):

Cell Death ◽

Tumor Growth ◽

Er Stress ◽

Cell Survival ◽

Glucose Levels ◽

Lower Glucose ◽

Low Glucose ◽

Glucose Availability

SummaryN-acetylasparate (NAA), previously considered a brain-specific metabolite, is found in several cancers. However, whether it plays a role in tumor growth or survival is not fully understood. We provide evidence that NAA prevents cell death in low-glucose conditions via sustaining intracellular UDP-N-acetylglucosamine (UDP-GlcNac) levels, suppressing endoplasmic reticulum (ER) stress, and enabling continued protein synthesis. NAA production is critical for in vivo tumor growth where lower glucose levels are present than those in cell culture. Furthermore, the breakdown of NAA leads to ER stress and cell death, suggesting that the role of NAA in low-glucose is independent of its catabolism to produce aspartate or acetate. Together, these data suggest NAA can support the growth of some tumors by helping them cope with glucose limitations in vivo.HighlightsEndogenous N-acetylaspartate (NAA) production boosts tumor growthNAA supports cell survival in low glucose via suppressing ER stressBreaking down NAA limits tumor growth and induces ER stress in vivoThe role of NAA to rescue low glucose is independent of donating acetate or aspartateIn briefCancer cells need N-acetylaspartate to avoid ER stress and cell death when glucose availability is low.

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Autophagy as a modulator of cell death machinery

Cell Death and Disease ◽

10.1038/s41419-020-2724-5 ◽

2020 ◽

Vol 11 (7) ◽

Cited By ~ 6

Author(s):

Masayuki Noguchi ◽

Noriyuki Hirata ◽

Tsutomu Tanaka ◽

Futoshi Suizu ◽

Hiroshi Nakajima ◽

...

Keyword(s):

Cell Death ◽

Cell Survival ◽

Mammalian Cells ◽

Critical Parameter ◽

Type I ◽

Type Ii ◽

Critical Question ◽

A Cell ◽

Underlying Mechanisms

Abstract The balance between cell death and survival is a critical parameter in the regulation of cells and the maintenance of homeostasis in vivo. Three major mechanisms for cell death have been identified in mammalian cells: apoptosis (type I), autophagic cell death (type II), and necrosis (type III). These three mechanisms have been suggested to engage in cross talk with each other. Among them, autophagy was originally characterized as a cell survival mechanism for amino acid recycling during starvation. Whether autophagy functions primarily in cell survival or cell death is a critical question yet to be answered. Here, we present a comprehensive review of the cell death-related events that take place during autophagy and their underlying mechanisms in cancer and autoimmune disease development.

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LINC-PINT impedes DNA repair and enhances radiotherapeutic response by targeting DNA-PKcs in nasopharyngeal cancer

Cell Death and Disease ◽

10.1038/s41419-021-03728-2 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

You-hong Wang ◽

Zhen Guo ◽

Liang An ◽

Yong Zhou ◽

Heng Xu ◽

...

Keyword(s):

Dna Damage ◽

Nasopharyngeal Cancer ◽

Noncoding Rnas ◽

Dependent Protein Kinase ◽

Damage Repair ◽

Dependent Protein ◽

Cancer Tissues

AbstractRadioresistance continues to be the leading cause of recurrence and metastasis in nasopharyngeal cancer. Long noncoding RNAs are emerging as regulators of DNA damage and radioresistance. LINC-PINT was originally identified as a tumor suppressor in various cancers. In this study, LINC-PINT was significantly downregulated in nasopharyngeal cancer tissues than in rhinitis tissues, and low LINC-PINT expressions showed poorer prognosis in patients who received radiotherapy. We further identified a functional role of LINC-PINT in inhibiting the malignant phenotypes and sensitizing cancer cells to irradiation in vitro and in vivo. Mechanistically, LINC-PINT was responsive to DNA damage, inhibiting DNA damage repair through ATM/ATR-Chk1/Chk2 signaling pathways. Moreover, LINC-PINT increased radiosensitivity by interacting with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and negatively regulated the expression and recruitment of DNA-PKcs. Therefore, these findings collectively support the possibility that LINC-PINT serves as an attractive target to overcome radioresistance in NPC.

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Topoisomerase II is regulated by translationally controlled tumor protein for cell survival during organ growth in Drosophila

Cell Death and Disease ◽

10.1038/s41419-021-04091-y ◽

2021 ◽

Vol 12 (9) ◽

Author(s):

Dae-Wook Yang ◽

Jung-Wan Mok ◽

Stephanie B. Telerman ◽

Robert Amson ◽

Adam Telerman ◽

...

Keyword(s):

Cell Survival ◽

Topoisomerase Ii ◽

Wing Disc ◽

Organ Development ◽

Translationally Controlled Tumor Protein ◽

Protein Levels ◽

Eye Disc ◽

Mutual Regulation

AbstractRegulation of cell survival is critical for organ development. Translationally controlled tumor protein (TCTP) is a conserved protein family implicated in the control of cell survival during normal development and tumorigenesis. Previously, we have identified a human Topoisomerase II (TOP2) as a TCTP partner, but its role in vivo has been unknown. To determine the significance of this interaction, we examined their roles in developing Drosophila organs. Top2 RNAi in the wing disc leads to tissue reduction and caspase activation, indicating the essential role of Top2 for cell survival. Top2 RNAi in the eye disc also causes loss of eye and head tissues. Tctp RNAi enhances the phenotypes of Top2 RNAi. The depletion of Tctp reduces Top2 levels in the wing disc and vice versa. Wing size is reduced by Top2 overexpression, implying that proper regulation of Top2 level is important for normal organ development. The wing phenotype of Tctp RNAi is partially suppressed by Top2 overexpression. This study suggests that mutual regulation of Tctp and Top2 protein levels is critical for cell survival during organ development.

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YAP inhibits autophagy and promotes progression of colorectal cancer via upregulating Bcl-2 expression

Cell Death and Disease ◽

10.1038/s41419-021-03722-8 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Lan Jin ◽

Yunhe Chen ◽

Dan Cheng ◽

Zhikai He ◽

Xinyi Shi ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Death ◽

Transcriptional Coactivator ◽

Inhibitory Protein ◽

Potential Therapeutic Target ◽

Related Cell ◽

Autophagy Inhibition

AbstractColorectal cancer (CRC) is one of the most aggressive and lethal cancers. The role of autophagy in the pathobiology of CRC is intricate, with opposing functions manifested in different cellular contexts. The Yes-associated protein (YAP), a transcriptional coactivator inactivated by the Hippo tumor-suppressor pathway, functions as an oncoprotein in a variety of cancers. In this study, we found that YAP could negatively regulate autophagy in CRC cells, and consequently, promote tumor progression of CRC in vitro and in vivo. Mechanistically, YAP interacts with TEAD forming a complex to upregulate the transcription of the apoptosis-inhibitory protein Bcl-2, which may subsequently facilitate cell survival by suppressing autophagy-related cell death; silencing Bcl-2 expression could alleviate YAP-induced autophagy inhibition without affecting YAP expression. Collectively, our data provide evidence for YAP/Bcl-2 as a potential therapeutic target for drug exploration against CRC.

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PapRIV, a BV-2 microglial cell activating quorum sensing peptide

Scientific Reports ◽

10.1038/s41598-021-90030-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yorick Janssens ◽

Nathan Debunne ◽

Anton De Spiegeleer ◽

Evelien Wynendaele ◽

Marta Planas ◽

...

Keyword(s):

Quorum Sensing ◽

Cell Model ◽

Dependent Manner ◽

Communication Signals ◽

Gram Positive Bacteria ◽

A Cell ◽

Gastro Intestinal Tract

AbstractQuorum sensing peptides (QSPs) are bacterial peptides produced by Gram-positive bacteria to communicate with their peers in a cell-density dependent manner. These peptides do not only act as interbacterial communication signals, but can also have effects on the host. Compelling evidence demonstrates the presence of a gut-brain axis and more specifically, the role of the gut microbiota in microglial functioning. The aim of this study is to investigate microglial activating properties of a selected QSP (PapRIV) which is produced by Bacillus cereus species. PapRIV showed in vitro activating properties of BV-2 microglia cells and was able to cross the in vitro Caco-2 cell model and reach the brain. In vivo peptide presence was also demonstrated in mouse plasma. The peptide caused induction of IL-6, TNFα and ROS expression and increased the fraction of ameboid BV-2 microglia cells in an NF-κB dependent manner. Different metabolites were identified in serum, of which the main metabolite still remained active. PapRIV is thus able to cross the gastro-intestinal tract and the blood–brain barrier and shows in vitro activating properties in BV-2 microglia cells, hereby indicating a potential role of this quorum sensing peptide in gut-brain interaction.

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Mitochondrion-Dependent Cell Death in TDP-43 Proteinopathies

Biomedicines ◽

10.3390/biomedicines9040376 ◽

2021 ◽

Vol 9 (4) ◽

pp. 376

Author(s):

Chantal B. Lucini ◽

Ralf J. Braun

Keyword(s):

Cell Death ◽

Oxygen Species ◽

In Vivo Models ◽

Dependent Cell ◽

Cell Death Mechanisms ◽

Sting Pathway ◽

Mitochondrial Membrane Permeabilization

In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.

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Role of PARP Under Stress Conditions: Cell Death or Protection?

Neurochemical Research ◽

10.1023/a:1022316914492 ◽

2003 ◽

Vol 28 (2) ◽

pp. 187-194 ◽

Cited By ~ 35

Author(s):

Vincenzo Giuseppe Nicoletti ◽

Anna Maria Giuffrida Stella

Keyword(s):

Cell Death ◽

Stress Conditions

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Role of long-chain acyl-CoAs in the regulation of mycolic acid biosynthesis in mycobacteria

Open Biology ◽

10.1098/rsob.170087 ◽

2017 ◽

Vol 7 (7) ◽

pp. 170087 ◽

Cited By ~ 10

Author(s):

Yi Ting Tsai ◽

Valentina Salzman ◽

Matías Cabruja ◽

Gabriela Gago ◽

Hugo Gramajo

Keyword(s):

Cell Envelope ◽

Phospholipid Composition ◽

Mycolic Acid ◽

Transcriptional Level ◽

Direct Role ◽

Conditional Mutant ◽

In The Wild ◽

Fas Ii

One of the dominant features of the biology of Mycobacterium tuberculosis , and other mycobacteria, is the mycobacterial cell envelope with its exceptional complex composition. Mycolic acids are major and very specific components of the cell envelope and play a key role in its architecture and impermeability. Biosynthesis of mycolic acid (MA) precursors requires two types of fatty acid synthases, FAS I and FAS II, which should work in concert in order to keep lipid homeostasis tightly regulated. Both FAS systems are regulated at their transcriptional level by specific regulatory proteins. FasR regulates components of the FAS I system, whereas MabR and FadR regulate components of the FAS II system. In this article, by constructing a tight mabR conditional mutant in Mycobacterium smegmatis mc 2 155, we demonstrated that sub-physiological levels of MabR lead to a downregulation of the fasII genes, inferring that this protein is a transcriptional activator of the FAS II system. In vivo labelling experiments and lipidomic studies carried out in the wild-type and the mabR conditional mutant demonstrated that under conditions of reduced levels of MabR, there is a clear inhibition of biosynthesis of MAs, with a concomitant change in their relative composition, and of other MA-containing molecules. These studies also demonstrated a change in the phospholipid composition of the membrane of the mutant strain, with a significant increase of phosphatidylinositol. Gel shift assays carried out with MabR and P fasII as a probe in the presence of different chain-length acyl-CoAs strongly suggest that molecules longer than C 18 can be sensed by MabR to modulate its affinity for the operator sequences that it recognizes, and in that way switch on or off the MabR-dependent promoter. Finally, we demonstrated the direct role of MabR in the upregulation of the fasII operon genes after isoniazid treatment.

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