scholarly journals At the Crossroads of Apoptosis and Autophagy: Multiple Roles of the Co-Chaperone BAG3 in Stress and Therapy Resistance of Cancer

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 574 ◽  
Author(s):  
Donat Kögel ◽  
Benedikt Linder ◽  
Andreas Brunschweiger ◽  
Silvia Chines ◽  
Christian Behl
Keyword(s):  
Stress Responses ◽  
Physiological Role ◽  
Proteasomal Degradation ◽  
Therapy Resistance ◽  
Major Protein ◽  
Cytoskeletal Dynamics ◽  
Cellular Stress Responses ◽  
Function Expression ◽  
Client Proteins ◽  
The One

BAG3, a multifunctional HSP70 co-chaperone and anti-apoptotic protein that interacts with the ATPase domain of HSP70 through its C-terminal BAG domain plays a key physiological role in cellular proteostasis. The HSP70/BAG3 complex determines the levels of a large number of selective client proteins by regulating their turnover via the two major protein degradation pathways, i.e. proteasomal degradation and macroautophagy. On the one hand, BAG3 competes with BAG1 for binding to HSP70, thereby preventing the proteasomal degradation of its client proteins. By functionally interacting with HSP70 and LC3, BAG3 also delivers polyubiquitinated proteins to the autophagy pathway. BAG3 exerts a number of key physiological functions, including an involvement in cellular stress responses, proteostasis, cell death regulation, development, and cytoskeletal dynamics. Conversely, aberrant BAG3 function/expression has pathophysiological relevance correlated to cardiomyopathies, neurodegeneration, and cancer. Evidence obtained in recent years underscores the fact that BAG3 drives several key hallmarks of cancer, including cell adhesion, metastasis, angiogenesis, enhanced autophagic activity, and apoptosis inhibition. This review provides a state-of-the-art overview on the role of BAG3 in stress and therapy resistance of cancer, with a particular focus on BAG3-dependent modulation of apoptotic signaling and autophagic/lysosomal activity.

The neutral sphingomyelinase 2 in T cell receptor signaling and polarity

2018 ◽  
Vol 399 (10) ◽  
pp. 1147-1155 ◽  
Author(s):  
Lena Collenburg ◽  
Sibylle Schneider-Schaulies ◽  
Elita Avota
Keyword(s):  
T Cell ◽  
Stress Responses ◽  
Synapse Formation ◽  
Immune Cell ◽  
Cell Receptor ◽  
Immune Synapse ◽  
Neutral Sphingomyelinase ◽  
Cytoskeletal Dynamics ◽  
Cellular Stress Responses

AbstractBy hydrolyzing its substrate sphingomyelin at the cytosolic leaflet of cellular membranes, the neutral sphingomyelinase 2 (NSM2) generates microdomains which serve as docking sites for signaling proteins and thereby, functions to regulate signal relay. This has been particularly studied in cellular stress responses while the regulatory role of this enzyme in the immune cell compartment has only recently emerged. In T cells, phenotypic polarization by co-ordinated cytoskeletal remodeling is central to motility and interaction with endothelial or antigen-presenting cells during tissue recruitment or immune synapse formation, respectively. This review highlights studies adressing the role of NSM2 in T cell polarity in which the enzyme plays a major role in regulating cytoskeletal dynamics.

scholarly journals Flavonoids: Potential Candidates for the Treatment of Neurodegenerative Disorders

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 99
Author(s):  
Shweta Devi ◽  
Vijay Kumar ◽  
Sandeep Kumar Singh ◽  
Ashish Kant Dubey ◽  
Jong-Joo Kim
Keyword(s):  
Stress Response ◽  
Stress Responses ◽  
Neurodegenerative Disorders ◽  
Cell Damage ◽  
Cellular Stress ◽  
Clinical Manifestations ◽  
Cellular Stress Response ◽  
Dramatic Rise ◽  
Cellular Stress Responses

Neurodegenerative disorders, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD), are the most concerning disorders due to the lack of effective therapy and dramatic rise in affected cases. Although these disorders have diverse clinical manifestations, they all share a common cellular stress response. These cellular stress responses including neuroinflammation, oxidative stress, proteotoxicity, and endoplasmic reticulum (ER)-stress, which combats with stress conditions. Environmental stress/toxicity weakened the cellular stress response which results in cell damage. Small molecules, such as flavonoids, could reduce cellular stress and have gained much attention in recent years. Evidence has shown the potential use of flavonoids in several ways, such as antioxidants, anti-inflammatory, and anti-apoptotic, yet their mechanism is still elusive. This review provides an insight into the potential role of flavonoids against cellular stress response that prevent the pathogenesis of neurodegenerative disorders.

scholarly journals CRISPR-Mediated Endogenous Activation of Fibroin Heavy Chain Gene Triggers Cellular Stress Responses in Bombyx mori Embryonic Cells

Insects ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 552
Author(s):  
Wenbo Hu ◽  
Xiaogang Wang ◽  
Sanyuan Ma ◽  
Zhangchuan Peng ◽  
Yang Cao ◽  
...  
Keyword(s):  
Bombyx Mori ◽  
Heavy Chain ◽  
Stress Responses ◽  
Cellular Stress ◽  
Silk Gland ◽  
Cellular Stress Response ◽  
Molar Ratio ◽  
Chain Gene ◽  
Gland Cells ◽  
Cellular Stress Responses

The silkworm Bombyx mori is an economically important insect, as it is the main producer of silk. Fibroin heavy chain (FibH) gene, encoding the core component of silk protein, is specifically and highly expressed in silk gland cells but not in the other cells. Although the silkworm FibH gene has been well studied in transcriptional regulation, its biological functions in the development of silk gland cells remain elusive. In this study, we constructed a CRISPRa system to activate the endogenous transcription of FibH in Bombyx mori embryonic (BmE) cells, and the mRNA expression of FibH was successfully activated. In addition, we found that FibH expression was increased to a maximum at 60 h after transient transfection of sgRNA/dCas9-VPR at a molar ratio of 9:1. The qRT-PCR analysis showed that the expression levels of cellular stress response-related genes were significantly up-regulated along with activated FibH gene. Moreover, the lyso-tracker red and monodansylcadaverine (MDC) staining assays revealed an apparent appearance of autophagy in FibH-activated BmE cells. Therefore, we conclude that the activation of FibH gene leads to up-regulation of cellular stress responses-related genes in BmE cells, which is essential for understanding silk gland development and the fibroin secretion process in B. mori.

scholarly journals Cellular Stress Responses: A Balancing Act

2010 ◽  
Vol 40 (2) ◽  
pp. 175 ◽  
Author(s):  
Feng Chen ◽  
Allyson Evans ◽  
John Pham ◽  
Brian Plosky
Keyword(s):  
Stress Responses ◽  
Cellular Stress ◽  
Cellular Stress Responses

scholarly journals The Phosphorylation-Dependent Regulation of Mitochondrial Proteins in Stress Responses

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Yusuke Kanamaru ◽  
Shiori Sekine ◽  
Hidenori Ichijo ◽  
Kohsuke Takeda
Keyword(s):  
Stress Responses ◽  
Map Kinases ◽  
Mitochondrial Fission ◽  
Cellular Stress ◽  
Degradation Process ◽  
Mitochondrial Proteins ◽  
Phosphoglycerate Mutase ◽  
Mitogen Activated Protein ◽  
Cellular Stress Responses ◽  
Autophagic Degradation

To maintain cellular homeostasis, cells are equipped with precise systems that trigger the appropriate stress responses. Mitochondria not only provide cellular energy but also integrate stress response signaling pathways, including those regulating cell death. Several lines of evidence suggest that the mitochondrial proteins that function in this process, such as Bcl-2 family proteins in apoptosis and phosphoglycerate mutase family member 5 (PGAM5) in necroptosis, are regulated by several kinases. It has also been suggested that the phosphorylation-dependent regulation of mitochondrial fission machinery, dynamin-related protein 1 (Drp1), facilitates appropriate cellular stress responses. However, mitochondria themselves are also damaged by various stresses. To avoid the deleterious effects exerted by damaged mitochondria, cells remove these mitochondria in a selective autophagic degradation process called mitophagy. Interestingly, several kinases, such as PTEN-induced putative kinase 1 (PINK1) in mammals and stress-responsive mitogen-activated protein (MAP) kinases in yeast, have recently been shown to be involved in mitophagy. In this paper, we focus on the phosphorylation-dependent regulation of mitochondrial proteins and discuss the roles of this regulation in the mitochondrial and cellular stress responses.

scholarly journals Differential regulation of cellular stress responses by the endoplasmic reticulum-resident Selenoprotein S (Seps1) in proliferating myoblasts versus myotubes

2018 ◽  
Vol 6 (24) ◽  
pp. e13926 ◽  
Author(s):  
Alex B. Addinsall ◽  
Sheree D. Martin ◽  
Fiona Collier ◽  
Xavier A. Conlan ◽  
Victoria C. Foletta ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Responses ◽  
Cellular Stress ◽  
Differential Regulation ◽  
Selenoprotein S ◽  
Cellular Stress Responses

scholarly journals G9a/GLP methyltransferases inhibit autophagy by methylation-mediated ATG12 protein degradation

2021 ◽  
Author(s):  
Chang-Hoon Kim ◽  
Kyung-Tae Park ◽  
Sang-Hun Lee
Keyword(s):  
Protein Degradation ◽  
Stress Responses ◽  
Methylation Status ◽  
Stress Conditions ◽  
Post Translational Modification ◽  
Autophagy Induction ◽  
Molecular Rheostat ◽  
Intracellular Ca ◽  
Lysine Methyltransferase ◽  
Cellular Stress Responses

ABSTRACTPrevious studies have shown that G9a, a lysine methyltransferase, inhibits autophagy by repressing the transcription of autophagy genes. Here, we demonstrate a novel mechanism whereby G9a/GLP inhibit autophagy through post-translational modification of ATG12, a protein critical for the initiation of autophagosome formation. Under non-stress conditions, G9a/GLP directly methylate ATG12. The methylated ATG12 undergoes ubiquitin-mediated protein degradation, thereby inhibiting autophagy induction. By contrast, under stress conditions that elevate intracellular Ca2+ levels, the activated calpain system cleaves the G9a/GLP proteins, leading to G9a/GLP protein degradation. The reduced G9a/GLP levels allow ATG12 to accumulate and form the ATG12-ATG5 conjugate, thus expediting autophagy initiation. Collectively, our findings reveal a distinct signaling pathway that links cellular stress responses involving Ca2+/calpain to G9a/GLP-mediated autophagy regulation. Moreover, our model proposes that the methylation status of ATG12 is a molecular rheostat that controls autophagy induction.

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