scholarly journals IP3R-driven increases in mitochondrial Ca2+ promote neuronal death in NPC disease

2021 ◽  
Vol 118 (40) ◽  
pp. e2110629118
Author(s):  
Scott A. Tiscione ◽  
Maria Casas ◽  
Jonathan D. Horvath ◽  
Vincent Lam ◽  
Keiko Hino ◽  
...  
Keyword(s):  
Neuronal Death ◽  
Intracellular Signaling ◽  
Signaling Cascades ◽  
Presenilin 1 ◽  
Signaling Cascade ◽  
Molecular Pathways ◽  
Loss Of Function ◽  
Signaling Axis ◽  
Niemann Pick

Ca2+ is the most ubiquitous second messenger in neurons whose spatial and temporal elevations are tightly controlled to initiate and orchestrate diverse intracellular signaling cascades. Numerous neuropathologies result from mutations or alterations in Ca2+ handling proteins; thus, elucidating molecular pathways that shape Ca2+ signaling is imperative. Here, we report that loss-of-function, knockout, or neurodegenerative disease–causing mutations in the lysosomal cholesterol transporter, Niemann-Pick Type C1 (NPC1), initiate a damaging signaling cascade that alters the expression and nanoscale distribution of IP3R type 1 (IP3R1) in endoplasmic reticulum membranes. These alterations detrimentally increase Gq-protein coupled receptor–stimulated Ca2+ release and spontaneous IP3R1 Ca2+ activity, leading to mitochondrial Ca2+ cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IP3R1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca2+ phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IP3R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease.

scholarly journals Visfatin: A Possible Role in Cardiovasculo-Metabolic Disorders

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2444
Author(s):  
Ali Dakroub ◽  
Suzanne A. Nasser ◽  
Nour Younis ◽  
Humna Bhagani ◽  
Yusra Al-Dhaheri ◽  
...  
Keyword(s):  
Nicotinamide Adenine Dinucleotide ◽  
Intracellular Signaling ◽  
Skeletal Muscles ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Signaling Cascades ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Enhancing Factor ◽  
Cell Colony

Visfatin/NAMPT (nicotinamide phosphoribosyltransferase) is an adipocytokine with several intriguing properties. It was first identified as pre-B-cell colony-enhancing factor but turned out to possess enzymatic functions in nicotinamide adenine dinucleotide biosynthesis, with ubiquitous expression in skeletal muscles, liver, cardiomyocytes, and brain cells. Visfatin exists in an intracellular (iNAMPT) and extracellular (eNAMPT) form. Intracellularly, visfatin/iNAMPT plays a regulatory role in NAD+ biosynthesis and thereby affects many NAD-dependent proteins such as sirtuins, PARPs, MARTs and CD38/157. Extracellularly, visfatin is associated with many hormone-like signaling pathways and activates some intracellular signaling cascades. Importantly, eNAMPT has been associated with several metabolic disorders including obesity and type 1 and 2 diabetes. In this review, a brief overview about visfatin is presented with special emphasis on its relevance to metabolic diseases. Visfatin/NAMPT appears to be a unique molecule with clinical significance with a prospective promising diagnostic, prognostic, and therapeutic applications in many cardiovasculo-metabolic disorders.

scholarly journals Absence of Mal/TIRAP Results in Abrogated Imidazoquinolinones-Dependent Activation of IRF7 and Suppressed IFNβ and IFN-I Activated Gene Production

2020 ◽  
Vol 21 (23) ◽  
pp. 8925
Author(s):  
Ewa Leszczyńska ◽  
Edyta Makuch ◽  
Małgorzata Mitkiewicz ◽  
Izabella Jasyk ◽  
Miwako Narita ◽  
...  
Keyword(s):  
Immune Response ◽  
Transcription Factor ◽  
Intracellular Signaling ◽  
Innate Immune ◽  
Signaling Cascades ◽  
Signaling Cascade ◽  
Type I ◽  
Type I Ifns ◽  
Activation Of Transcription ◽  
Intracellular Signaling Molecules

Activation of TLR7 by small imidazoquinoline molecules such as R848 or R837 initiates signaling cascades leading to the activation of transcription factors, such as AP-1, NF-κB, and interferon regulatory factors (IRFs) and afterward to the induction of cytokines and anti-viral Type I IFNs. In general, TLRs mediate these effects by utilizing different intracellular signaling molecules, one of them is Mal. Mal is a protein closely related to the antibacterial response, and its role in the TLR7 pathways remains poorly understood. In this study, we show that Mal determines the expression and secretion of IFNβ following activation of TLR7, a receptor that recognizes ssRNA and imidazoquinolines. Moreover, we observed that R848 induces Mal-dependent IFNβ production via ERK1/2 activation as well as the transcription factor IRF7 activation. Although activation of TLR7 leads to NF-κB-dependent expression of IRF7, this process is independent of Mal. We also demonstrate that secretion of IFNβ regulated by TLR7 and Mal in macrophages and dendritic cells leads to the IP-10 chemokine expression. In conclusion, our data demonstrate that Mal is a critical regulator of the imidazoquinolinones-dependent IFNβ production via ERK1/2/IRF7 signaling cascade which brings us closer to understanding the molecular mechanism’s regulation of innate immune response.

scholarly journals Toll-like receptors activation, signaling, and targeting: an overview

2019 ◽  
Vol 43 (1) ◽  
Author(s):  
Salwa Refat El-Zayat ◽  
Hiba Sibaii ◽  
Fathia A. Mannaa
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Inflammatory Diseases ◽  
Host Cells ◽  
Signaling Cascades ◽  
Innate Immune Responses ◽  
Toll Like Receptors ◽  
Tlr Signaling ◽  
Dying Cells

Abstract Background Toll-like receptors (TLRs) are an important family of receptors that constitute the first line of defense system against microbes. They can recognize both invading pathogens and endogenous danger molecules released from dying cells and damaged tissues and play a key role in linking innate and adaptive immunity. TLRs are widely distributed in both immune and other body cells. The expressions and locations of TLRs are regulated in response to specific molecules derived from pathogens or damaged host cells. The binding of ligands to TLR activates specific intracellular signaling cascades that initiate host defense reactions. Such binding is ligand-dependent and cell type-dependent and leads to production of pro-inflammatory cytokines and type 1 interferon. TLR-dependent signaling pathways are tightly increased during innate immune responses by a variety of negative regulators. Overactivation of TLRs can ultimately lead to disruption of immune homeostasis and thus increase the risk for inflammatory diseases and autoimmune disorders. Antagonists/inhibitors targeting the TLR signaling pathways have emerged as novel therapeutics to treat these diseases. Aim of work The present review summarizes the structure, characterizations, and signaling of TLRs and their regulators, as well as describes the implication of TLRs in many diseases with a brief idea about the inhibitors that target TLR signaling pathways. Conclusion We conclude that TLRs are the main elements of our immune system, and they should be maintained functioning to keep the integrity of innate immunity. Targeting of TLR signaling represents a new challenge for treatment of many diseases.

scholarly journals Targeting Intracellular Signaling Cascades for Patients with Relapsed, Refractory Multiple Myeloma: A Systematic Review of Clinical Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5659-5659
Author(s):  
Shehroz Aslam ◽  
Mustafa Nadeem Malik ◽  
Abdul Rafae ◽  
Rida Riaz ◽  
Seren Durer ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Phase Ii ◽  
Intracellular Signaling ◽  
Single Agent ◽  
Mek Inhibitor ◽  
Signaling Cascades ◽  
Signaling Cascade ◽  
Best Response ◽  
Combination Regimens

Abstract Introduction: Intracellular signaling cascades including mTOR (mammalian target of rapamycin), MEK (mitogen-activated protein kinase), BCL2 (B-cell lymphoma 2), MET, AKT, and BTK (Bruton's tyrosine kinase) pathways are involved in the growth, proliferation, and survival of tumor cells. Drugs that inhibit these signaling cascades lead to apoptosis and cell cycle arrest making them an important therapeutic modality for treatment of malignancies. The aim of our review is to analyze the published literature on the clinical efficacy of these intracellular signaling cascade inhibitors in patients with relapsed, refractory multiple myeloma (RRMM). Methods: We performed a comprehensive literature search on articles published after 2010. Four hundred and twenty-three articles were identified using the following five databases (Pubmed, Embase Cochrane, Web of Science and Clinical Trials.gov). After a detailed screening, we finalized 11 studies involving 525 RRMM patients. Clinical trials (phase I/II, II and III) with non-FDA approved drugs were included. Results: mTOR inhibitors (Everolimus and Temsirolimus): A total of 157 RRMM patients were included. All trials were early phase (I/II). Everolimus in combination with panobinostat (n=32) achieved an overall response rate (ORR) of 7%. A total of 82 patients received everolimus in combination with sorafenib and achieved a complete response (CR) of 8.5%. Temsirolimus was used in combination with bortezomib (V) (n=43). CR was observed in 5% patients, very good partial response (VGPR) in 9% and stable disease (SD) in 44% patients. AKT Inhibitors (Perifosine and Uprosertib): A total of 153 RRMM patients were included. Eighty-four patients were tested in phase I/II trials while 69 patients were tested in phase III trials. All patients were given perifosine (50 mg) in combination with V with or without dexamethasone (d). In 142 evaluable patients, the pooled ORR was 31%. Uprosertib is currently under phase II evaluation, no clinical data is available while one ongoing phase I/II trial is summarized in Table 2. MEK inhibitor (Selumetinib): A total of 36 RRMM patients were included. All patients were tested in phase II trials. Single-agent selumetinib (75 mg) was given (n= 32). The ORR was 5.6%, VGPR in 3.12%, partial response (PR) in 3.12%, SD in 53.13% and progressive disease (PD) in 40.63% patients. The median progression-free survival (mPFS) was 3.52 months. BCL2 inhibitor (Venetoclax): A total of 66 RRMM patients were included. All patients were tested in phase I/II trials. Single-agent venetoclax (300-1200 mg) was given. The ORR was 21%, CR in 4%, VGPR in 8% and PR in 6% patients. MET inhibitors (Cabozantinib and Tivantinib): A total of 27 RRMM patients were included. Eleven patients were tested in phase I/II trials while 16 patients were tested in phase II trial. Cabozantinib (20-60 mg) and Tivantinib (360 mg) were given to 11 and 16 patients respectively. SD was seen in 54.5% and 36% patients respectively while PD was seen in 18.2% and 63% patients respectively. BTK inhibitor (Ibrutinib): A total of 86 RRMM patients were included. Patients were tested in phase I/II (n=46) and phase II (n=46) clinical trials. Ibrutinib (560-840 mg) was used in combination regimens in all patients. In 85 evaluable patients, the pooled ORR was 35.29%. The best response was seen when ibrutininb was used in combination with carfilzomib (CFZ) with or without dexamethasone (d) i.e. 67%. Conclusion: In RRMM patients, BTK inhibitor (ibrutinib) and AKT inhibitor (perifosine) when used in combination regimens demonstrated a weak efficacy with an ORR of < 40%. The best response was seen when ibrutinib was used in combination with CFZ +/- d i.e. 67%. MET inhibitor (cabozantinib) and MEK inhibitor (selumetinib) showed SD in more than 50% of patients. mTOR inhibitor (temsirolimus) showed SD in more than 40% of patients. Other intracellular signaling cascade inhibitors (venetoclax, selumetinib, everolimus) when used either as single agents or in combination regimens demonstrated a poor efficacy with an ORR of < 25%. However, data on signaling cascade inhibitors is emerging and future randomized prospective trials are needed. Disclosures No relevant conflicts of interest to declare.

scholarly journals Loss of presenilin function is associated with a selective gain of APP function

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Carole Deyts ◽  
Mary Clutter ◽  
Stacy Herrera ◽  
Natalia Jovanovic ◽  
Anna Goddi ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Neurite Outgrowth ◽  
Early Onset ◽  
Presenilin 1 ◽  
Signaling Cascade ◽  
Loss Of Function ◽  
Axonal Sprouting ◽  
Dominant Inheritance ◽  
Neurite Formation ◽  
Aβ Production

Presenilin 1 (PS1) is an essential γ-secretase component, the enzyme responsible for amyloid precursor protein (APP) intramembraneous cleavage. Mutations in PS1 lead to dominant-inheritance of early-onset familial Alzheimer’s disease (FAD). Although expression of FAD-linked PS1 mutations enhances toxic Aβ production, the importance of other APP metabolites and γ-secretase substrates in the etiology of the disease has not been confirmed. We report that neurons expressing FAD-linked PS1 variants or functionally deficient PS1 exhibit enhanced axodendritic outgrowth due to increased levels of APP intracellular C-terminal fragment (APP-CTF). APP expression is required for exuberant neurite outgrowth and hippocampal axonal sprouting observed in knock-in mice expressing FAD-linked PS1 mutation. APP-CTF accumulation initiates CREB signaling cascade through an association of APP-CTF with Gαs protein. We demonstrate that pathological PS1 loss-of-function impinges on neurite formation through a selective APP gain-of-function that could impact on axodendritic connectivity and contribute to aberrant axonal sprouting observed in AD patients.

scholarly journals Identification of NR5A1 (SF-1/AD4BP) gene expression modulators by large-scale gain and loss of function studies

2008 ◽  
Vol 198 (3) ◽  
pp. 489-497 ◽  
Author(s):  
Noriko Sakai ◽  
Hiromi Terami ◽  
Shinobu Suzuki ◽  
Megumi Haga ◽  
Ken Nomoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Signaling Cascades ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Group A ◽  
Tata Box Binding Protein

Nuclear receptor subfamily 5, group A, member 1 (NR5A1 previously known as SF-1/AD4BP) is a transcription factor involved in the development of adrenal/gonadal tissues and steroidogenic linage cell differentiation in adult somatic stem cells. To understand the cellular signaling network that regulates NR5A1 gene expression, loss of function screening with an siRNA kinome library, and gain of function screening with an addressable full-length cDNA library representing one quarter of the human genome was carried out. The NR5A1 gene expression was activated in mesenchymal stem cells by siRNA directed against protein kinase C (PKC)-δ, erb-B3, RhoGAP (ARHGAP26), and hexokinase 2, none of which were previously known to be involved in the NR5A1 gene expression. Among these, we identified crosstalk between erb-B3 and PKC-δ signaling cascades. In addition, the gain of function studies indicated that sex-determining region Y (SRY)-box 15 (SOX15), TEA domain family member 4, KIAA1257 (a gene of unknown function), ADAM metallopeptidase with thrombospondin type 1 motif 6, Josephin domain containing 1, centromere protein, TATA box-binding protein-associated factor 5-like RNA polymerase, and inducible T-cell co-stimulator activate NR5A1 gene expression. These results provide new insights into the molecular mechanisms of NR5A1 gene expression.

scholarly journals Integrin signaling via actin cytoskeleton activates MRTF/SRF to entrain circadian clock

2021 ◽  
Author(s):  
Ke Ma ◽  
Xuekai Xiong ◽  
Weini Li ◽  
Jin Nam
Keyword(s):  
Actin Cytoskeleton ◽  
Circadian Clock ◽  
Focal Adhesion ◽  
Intracellular Signaling ◽  
Actin Polymerization ◽  
Target Genes ◽  
Oscillation Amplitude ◽  
Actin Dynamics ◽  
Signaling Cascade ◽  
Loss Of Function

The circadian clock is entrained to daily environmental cues. Integrin-linked intracellular signaling via actin cytoskeleton dynamics transduces cellular niche signals to induce Myocardin-related Transcription Factor (MRTF)/Serum Response Factor (SRF)-mediated transcription. So far, how the integrin-associated signaling cascade may transmit cellular physical cues to entrain circadian clock remains to be defined. Using combined pharmacological and genetic approaches, here we show that the transcription factors mediating integrin to actin cytoskeleton signaling, MRTF-A and SRF, exert direct transcriptional control of core clock components, and that this signaling cascade modulates key properties of clock circadian activity. Pharmacological inhibition of MRTF/SRF activity by disrupting actin polymerization significantly augmented clock amplitude with period shortening , whereas an actin polymerizing compound attenuated oscillation amplitude with period lengthening. Genetic loss-of-function of Srf or Mrtf mimics that of actin-depolymerizing agents, validating the role of actin dynamics in driving clock function. Furthermore, integrin-mediated focal adhesion with extracellular matrix and its downstream signaling modulates the circadian clock, as blockade of integrin, focal adhesion kinase or Rho-associated kinase (ROCK) increased clock amplitude and shortened period length. Mechanistically, we identify specific core clock transcription regulators, Per1 , Per2 and Nr1d1 , as direct target genes of MRTF-A/SRF. Collectively, our findings uncovered an integrin-actin cytoskeleton-MRTF/SRF signaling cascade in linking clock entrainment to its extracellular microenvironment, which may mediate cellular adaptation to its physical niche.

scholarly journals Syntenin mediates SRC function in exosomal cell-to-cell communication

2017 ◽  
Vol 114 (47) ◽  
pp. 12495-12500 ◽  
Author(s):  
Naga Sailaja Imjeti ◽  
Kerstin Menck ◽  
Antonio Luis Egea-Jimenez ◽  
Celine Lecointre ◽  
Frederique Lembo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Intracellular Signaling ◽  
Cell Communication ◽  
Small Gtpase ◽  
Signaling Cascades ◽  
Current View ◽  
Loss Of Function ◽  
Surface Receptors ◽  
Host Interactions ◽  
Phospholipase D2

The cytoplasmic tyrosine kinase SRC controls cell growth, proliferation, adhesion, and motility. The current view is that SRC acts primarily downstream of cell-surface receptors to control intracellular signaling cascades. Here we reveal that SRC functions in cell-to-cell communication by controlling the biogenesis and the activity of exosomes. Exosomes are viral-like particles from endosomal origin that can reprogram recipient cells. By gain- and loss-of-function studies, we establish that SRC stimulates the secretion of exosomes having promigratory activity on endothelial cells and that syntenin is mandatory for SRC exosomal function. Mechanistically, SRC impacts on syndecan endocytosis and on syntenin–syndecan endosomal budding, upstream of ARF6 small GTPase and its effector phospholipase D2, directly phosphorylating the conserved juxtamembrane DEGSY motif of the syndecan cytosolic domain and syntenin tyrosine 46. Our study uncovers a function of SRC in cell–cell communication, supported by syntenin exosomes, which is likely to contribute to tumor–host interactions.

scholarly journals Maturation of the Na,K-ATPase in the Endoplasmic Reticulum in Health and Disease

2021 ◽  
Author(s):  
Vitalii Kryvenko ◽  
Olga Vagin ◽  
Laura A. Dada ◽  
Jacob I. Sznajder ◽  
István Vadász
Keyword(s):  
Endoplasmic Reticulum ◽  
Intracellular Signaling ◽  
Loss Of Function ◽  
Α Subunit ◽  
Rate Limiting Step ◽  
Atpase Subunits ◽  
A Cell ◽  
Health And Disease ◽  
And Function ◽  
Rate Limiting

Abstract The Na,K-ATPase establishes the electrochemical gradient of cells by driving an active exchange of Na+ and K+ ions while consuming ATP. The minimal functional transporter consists of a catalytic α-subunit and a β-subunit with chaperon activity. The Na,K-ATPase also functions as a cell adhesion molecule and participates in various intracellular signaling pathways. The maturation and trafficking of the Na,K-ATPase include co- and post-translational processing of the enzyme in the endoplasmic reticulum (ER) and the Golgi apparatus and subsequent delivery to the plasma membrane (PM). The ER folding of the enzyme is considered as the rate-limiting step in the membrane delivery of the protein. It has been demonstrated that only assembled Na,K-ATPase α:β-complexes may exit the organelle, whereas unassembled, misfolded or unfolded subunits are retained in the ER and are subsequently degraded. Loss of function of the Na,K-ATPase has been associated with lung, heart, kidney and neurological disorders. Recently, it has been shown that ER dysfunction, in particular, alterations in the homeostasis of the organelle, as well as impaired ER-resident chaperone activity may impede folding of Na,K-ATPase subunits, thus decreasing the abundance and function of the enzyme at the PM. Here, we summarize our current understanding on maturation and subsequent processing of the Na,K-ATPase in the ER under physiological and pathophysiological conditions. Graphic Abstract

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