scholarly journals Nox2 and Rac1 Regulate H2O2-Dependent Recruitment of TRAF6 to Endosomal Interleukin-1 Receptor Complexes

2006 ◽  
Vol 26 (1) ◽  
pp. 140-154 ◽  
Author(s):  
Qiang Li ◽  
Maged M. Harraz ◽  
Weihong Zhou ◽  
Liang N. Zhang ◽  
Wei Ding ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Interleukin 1 ◽  
Receptor Activation ◽  
Receptor Complex ◽  
Small Interfering Rnas ◽  
Cellular Mechanisms ◽  
Receptor Complexes ◽  
Endosomal Compartment ◽  
Plasma Membrane Receptor ◽  
Subcellular Compartmentalization

ABSTRACT Reactive oxygen species (ROS) generated by NADPH oxidases (Nox) have been implicated in the regulation of signal transduction. However, the cellular mechanisms that link Nox activation with plasma membrane receptor signaling remain poorly defined. We have found that Nox2-derived ROS influence the formation of an active interleukin-1 (IL-1) receptor complex in the endosomal compartment by directing the H2O2-dependent binding of TRAF6 to the IL-1R1/MyD88 complex. Clearance of both superoxide and H2O2 from within the endosomal compartment significantly abrogated IL-1β-dependent IKK and NF-κB activation. MyD88-dependent endocytosis of IL-1R1 following IL-1β binding was required for the redox-dependent formation of an active endosomal receptor complex competent for IKK and NF-κB activation. Small interfering RNAs to either MyD88 or Rac1 inhibited IL-1β induction of endosomal superoxide and NF-κB activation. However, MyD88 and Rac1 appear to be recruited independently to IL-1R1 following ligand stimulation. In this context, MyD88 binding was required for inducing endocytosis of IL-1R1 following ligand binding, while Rac1 facilitated the recruitment of Nox2 into the endosomal compartment and subsequent redox-dependent recruitment of TRAF6 to the MyD88/IL-1R1 complex. The identification of Nox-active endosomes helps explain how subcellular compartmentalization of redox signals can be used to direct receptor activation from the plasma membrane.

scholarly journals Plasma Membrane Receptor Complexes

2008 ◽  
Vol 147 (4) ◽  
pp. 1560-1564 ◽  
Author(s):  
José Aker ◽  
Sacco C. de Vries
Keyword(s):  
Plasma Membrane ◽  
Membrane Receptor ◽  
Receptor Complexes ◽  
Plasma Membrane Receptor

scholarly journals Interleukin-1 (IL-1) Receptor-Associated Kinase-Dependent IL-1-Induced Signaling Complexes Phosphorylate TAK1 and TAB2 at the Plasma Membrane and Activate TAK1 in the Cytosol

2002 ◽  
Vol 22 (20) ◽  
pp. 7158-7167 ◽  
Author(s):  
Zhengfan Jiang ◽  
Jun Ninomiya-Tsuji ◽  
Youcun Qian ◽  
Kunihiro Matsumoto ◽  
Xiaoxia Li
Keyword(s):  
Plasma Membrane ◽  
Complex I ◽  
Interleukin 1 ◽  
Critical Role ◽  
Complex Iii ◽  
Receptor Complex ◽  
Complex Ii ◽  
Jnk Activation ◽  
Cytosolic Factors ◽  
Sequential Formation

ABSTRACT Interleukin-1 (IL-1) receptor-associated kinase (IRAK) plays an important role in the sequential formation and activation of IL-1-induced signaling complexes. Previous studies showed that IRAK is recruited to the IL-1-receptor complex, where it is hyperphosphorylated. We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1, TAB1, and TAB2, which are preassociated on the membrane before stimulation to form the membrane-associated complex II. The formation of complex II leads to the phosphorylation of TAK1 and TAB2 on the membrane by an unknown kinase, followed by the dissociation of TRAF6-TAK1-TAB1-TAB2 (complex III) from IRAK and consequent translocation of complex III to the cytosol. The formation of complex III and its interaction with additional cytosolic factors lead to the activation of TAK1, resulting in NF-κB and JNK activation. Phosphorylated IRAK remains on the membrane and eventually is ubiquitinated and degraded. Taken together, the new data reveal that IRAK plays a critical role in mediating the association and dissociation of IL-1-induced signaling complexes, functioning as an organizer and transporter in IL-1-dependent signaling.

scholarly journals ATP-dependent activation of glucocorticoid receptor from rat liver cytosol

1980 ◽  
Vol 190 (3) ◽  
pp. 799-808 ◽  
Author(s):  
V K Moudgil ◽  
J K John
Keyword(s):  
Glucocorticoid Receptor ◽  
Rat Liver ◽  
Sodium Molybdate ◽  
Receptor Activation ◽  
Activation Process ◽  
Receptor Complex ◽  
Liver Cytosol ◽  
Receptor Complexes ◽  
Steroid Binding ◽  
Rat Liver Cytosol

The glucocorticoid—receptor complex from freshly prepared rat liver cytosol is in a non-activated form, with very little affinity to bind to isolated nuclei. When such preparations were incubated with 5—10 mM-ATP at 4 degrees C, the receptor complex acquired the properties of an ‘activated’ transformed form, which readily bound to nuclei, ATP—Sepharose, phosphocellulose and DNA—cellulose. This transformation was comparable with the activation achieved by warming the steroid—receptor complex at 23 degrees C. The effect of ATP was specific, as it was more effective than ADP, whereas AMP had no such effect on activation. The process of receptor activation was sensitive to the presence of 10 mM-sodium molybdate; the latter blocked activation by both ATP and heat. Bivalent cations had no observable effect on the receptor activation at low temperature, but they decreased the extent of activation by ATP. The steroid-binding properties of glucocorticoid receptor remained intact under the above conditions. However, a significant increase in steroid binding occurred when ATP was preincubated with cytosol receptor before the addition of [3H]triamcinolone acetonide. ATP also stabilized the glucocorticoid—receptor complexes at 23 degrees C. These results suggest a role for ATP in receptor function and offer a convenient method of studying the activation process of glucocorticoid receptor under mild assay conditions.

scholarly journals The Implications for Cells of the Lipid Switches Driven by Protein–Membrane Interactions and the Development of Membrane Lipid Therapy

2020 ◽  
Vol 21 (7) ◽  
pp. 2322 ◽  
Author(s):  
Manuel Torres ◽  
Catalina Ana Rosselló ◽  
Paula Fernández-García ◽  
Victoria Lladó ◽  
Or Kakhlon ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Membrane Lipids ◽  
Signal Propagation ◽  
Receptor Activation ◽  
Membrane Lipid ◽  
Physical Contact ◽  
Therapeutic Interventions ◽  
Signaling Proteins ◽  
Receptor Complexes ◽  
Peripheral Proteins

The cell membrane contains a variety of receptors that interact with signaling molecules. However, agonist–receptor interactions not always activate a signaling cascade. Amphitropic membrane proteins are required for signal propagation upon ligand-induced receptor activation. These proteins localize to the plasma membrane or internal compartments; however, they are only activated by ligand-receptor complexes when both come into physical contact in membranes. These interactions enable signal propagation. Thus, signals may not propagate into the cell if peripheral proteins do not co-localize with receptors even in the presence of messengers. As the translocation of an amphitropic protein greatly depends on the membrane’s lipid composition, regulation of the lipid bilayer emerges as a novel therapeutic strategy. Some of the signals controlled by proteins non-permanently bound to membranes produce dramatic changes in the cell’s physiology. Indeed, changes in membrane lipids induce translocation of dozens of peripheral signaling proteins from or to the plasma membrane, which controls how cells behave. We called these changes “lipid switches”, as they alter the cell’s status (e.g., proliferation, differentiation, death, etc.) in response to the modulation of membrane lipids. Indeed, this discovery enables therapeutic interventions that modify the bilayer’s lipids, an approach known as membrane-lipid therapy (MLT) or melitherapy.

scholarly journals Defective insulin receptor activation and altered lipid rafts in Niemann–Pick type C disease hepatocytes

2005 ◽  
Vol 391 (3) ◽  
pp. 465-472 ◽  
Author(s):  
Saara Vainio ◽  
Igor Bykov ◽  
Martin Hermansson ◽  
Eija Jokitalo ◽  
Pentti Somerharju ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Insulin Receptor ◽  
Lipid Rafts ◽  
Plasma Membranes ◽  
Cholesterol Content ◽  
Receptor Activation ◽  
Membrane Lipid ◽  
Plasma Membrane Receptor ◽  
Type C ◽  
Niemann Pick

Niemann–Pick type C (NPC) disease is a neuro-visceral cholesterol storage disorder caused by mutations in the NPC-1 or NPC-2 gene. In the present paper, we studied IR (insulin receptor) activation and the plasma-membrane lipid assembly in primary hepatocytes from control and NPC1–/– mice. We have previously reported that, in hepatocytes, IR activation is dependent on cholesterol–sphingolipid rafts [Vainio, Heino, Mansson, Fredman, Kuismanen, Vaarala and Ikonen (2002) EMBO Rep. 3, 95–100]. We found that, in NPC hepatocytes, IR levels were up-regulated and the receptor activation was compromised. Defective IR activation was reproduced in isolated NPC plasma-membrane preparations, which displayed an increased cholesterol content and saturation of major phospholipids. The NPC plasma membranes were less fluid than control membranes as indicated by increased DPH (1,6-diphenyl-1,3,5-hexatriene) fluorescence anisotropy values. Both in NPC hepatocytes and plasma-membrane fractions, the association of IR with low-density DRMs (detergent-resistant membranes) was increased. Moreover, the detergent resistance of both cholesterol and phosphatidylcholine were increased in NPC membranes. Finally, cholesterol removal inhibited IR activation in control membranes but restored IR activation in NPC membranes. Taken together, the results reveal a lipid imbalance in the NPC hepatocyte, which increases lipid ordering in the plasma membrane, alters the properties of lipid rafts and interferes with the function of a raft-associated plasma-membrane receptor. Such a mechanism may participate in the pathogenesis of NPC disease and contribute to insulin resistance in other disorders of lipid metabolism.

Regulation of protein sorting at the TGN by plasma membrane receptor activation

2000 ◽  
Vol 113 (4) ◽  
pp. 741-748 ◽  
Author(s):  
M. Baldassarre ◽  
A. Dragonetti ◽  
P. Marra ◽  
A. Luini ◽  
C. Isidoro ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cathepsin D ◽  
Leukemia Cell ◽  
Receptor Activation ◽  
Leukemia Cell Line ◽  
Major Player ◽  
Plasma Membrane Receptor ◽  
Immature Form ◽  
Secretory Lysosomes ◽  
Normal Processing

We show that in the rat basophilic leukemia cell line RBL, the physiological stimulation of the IgE receptor or direct activation of PKC leads to the missorting of proteins to the plasma membrane, diverting them from their normal intracellular destination. This is demonstrated for two classes of proteins that are normally targeted to the secretory lysosomes via completely different mechanisms, i.e. proteoglycans and the aspartic protease cathepsin D. In the latter case, normal processing of the enzyme is also affected, leading to secretion of the immature form of cathepsin. The present study shows how completely different sorting mechanisms, such as those for delivering proteoglycans and cathepsin D to secretory lysosomes, might share common regulatory signals and are similarly affected when the levels of these signals are perturbed. Finally, protein kinase C appears to be a major player in the signal transduction pathways, leading to proteoglycan and cathepsin D missorting.

scholarly journals Revising Endosomal Trafficking under Insulin Receptor Activation

2021 ◽  
Vol 22 (13) ◽  
pp. 6978
Author(s):  
Maria J. Iraburu ◽  
Tommy Garner ◽  
Cristina Montiel-Duarte
Keyword(s):  
Plasma Membrane ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
Small Gtpases ◽  
Early Endosome ◽  
Tyrosine Kinase Receptors ◽  
Endosomal Trafficking ◽  
Cell Functions

The endocytosis of ligand-bound receptors and their eventual recycling to the plasma membrane (PM) are processes that have an influence on signalling activity and therefore on many cell functions, including migration and proliferation. Like other tyrosine kinase receptors (TKR), the insulin receptor (INSR) has been shown to be endocytosed by clathrin-dependent and -independent mechanisms. Once at the early endosome (EE), the sorting of the receptor, either to the late endosome (LE) for degradation or back to the PM through slow or fast recycling pathways, will determine the intensity and duration of insulin effects. Both the endocytic and the endosomic pathways are regulated by many proteins, the Arf and Rab families of small GTPases being some of the most relevant. Here, we argue for a specific role for the slow recycling route, whilst we review the main molecular mechanisms involved in INSR endocytosis, sorting and recycling, as well as their possible role in cell functions.

scholarly journals Inhibition of MLKL-dependent necroptosis via downregulating interleukin-1R1 contributes to neuroprotection of hypoxic preconditioning in transient global cerebral ischemic rats

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lixuan Zhan ◽  
Xiaomei Lu ◽  
Wensheng Xu ◽  
Weiwen Sun ◽  
En Xu
Keyword(s):  
Plasma Membrane ◽  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Interleukin 1 ◽  
Hypoxic Preconditioning ◽  
Global Cerebral Ischemia ◽  
Free Calcium ◽  
Membrane Translocation ◽  
Vessel Occlusion ◽  
Transient Global Cerebral Ischemia

Abstract Background Our previous study indicated that hypoxic preconditioning reduced receptor interacting protein (RIP) 3-mediated necroptotic neuronal death in hippocampal CA1 of adult rats after transient global cerebral ischemia (tGCI). Although mixed lineage kinase domain-like (MLKL) has emerged as a crucial molecule for necroptosis induction downstream of RIP3, how MLKL executes necroptosis is not yet well understood. In this study, we aim to elucidate the molecular mechanism underlying hypoxic preconditioning that inactivates MLKL-dependent neuronal necroptosis after tGCI. Methods Transient global cerebral ischemia was induced by the four-vessel occlusion method. Twenty-four hours before ischemia, rats were exposed to systemic hypoxia with 8% O2 for 30 min. Western blotting was used to detect the expression of MLKL and interleukin-1 type 1 receptor (IL-1R1) in CA1. Immunoprecipitation was used to assess the interactions among IL-1R1, RIP3, and phosphorylated MLKL (p-MLKL). The concentration of intracellular free calcium ion (Ca2+) was measured using Fluo-4 AM. Silencing and overexpression studies were used to study the role of p-MLKL in tGCI-induced neuronal death. Results Hypoxic preconditioning decreased the phosphorylation of MLKL both in neurons and microglia of CA1 after tGCI. The knockdown of MLKL with siRNA decreased the expression of p-MLKL and exerted neuroprotective effects after tGCI, whereas treatment with lentiviral delivery of MLKL showed opposite results. Mechanistically, hypoxic preconditioning or MLKL siRNA attenuated the RIP3-p-MLKL interaction, reduced the plasma membrane translocation of p-MLKL, and blocked Ca2+ influx after tGCI. Furthermore, hypoxic preconditioning downregulated the expression of IL-1R1 in CA1 after tGCI. Additionally, neutralizing IL-1R1 with its antagonist disrupted the interaction between IL-1R1 and the necrosome, attenuated the expression and the plasma membrane translocation of p-MLKL, thus alleviating neuronal death after tGCI. Conclusions These data support that the inhibition of MLKL-dependent neuronal necroptosis through downregulating IL-1R1 contributes to neuroprotection of hypoxic preconditioning against tGCI.

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