scholarly journals M1-linked ubiquitination facilitates NF-κB activation during sterile inflammation

2021 ◽  
Author(s):  
Anna Aalto ◽  
Gabriela Martínez-Chacón ◽  
Nadezhda Tsyganova ◽  
Joose Kreutzer ◽  
Pasi Kallio ◽  
...  
Keyword(s):  
Mechanical Stress ◽  
Mammalian Cells ◽  
Inflammatory Diseases ◽  
Protective Action ◽  
Nuclear Factor Κb ◽  
Stress Conditions ◽  
Sterile Inflammation ◽  
Low Oxygen ◽  
Imd Pathway ◽  
Iκb Kinase

Methionine 1 (M1)-linked ubiquitination plays a key role in the regulation of inflammatory nuclear factor-κB (NF-κB) signalling and is important for clearance of pathogen infection in Drosophila melanogaster. M1-linked ubiquitin (M1-Ub) chains are assembled by the linear ubiquitin E3 ligase (LUBEL) in flies. Here, we have studied the role of LUBEL in sterile inflammation induced by different types of cellular stresses. We have found that LUBEL catalyses formation of M1-Ub chains in response to hypoxic, oxidative and mechanical stress conditions. LUBEL is shown to be important for flies to survive low oxygen conditions and paraquat-induced oxidative stress. This protective action seems to be driven by stress-induced activation of the NF-κB transcription factor Relish via the Immune deficiency (Imd) pathway. In addition to LUBEL, the intracellular mediators of Relish activation, including the Drosophila inhibitor of apoptosis (IAP) Diap2, the IκB kinase γ (IKKγ) Kenny and the initiator caspase Death-related ced-3/Nedd2-like protein (Dredd), but not the membrane receptor peptidoglycan recognition protein (PGRP)-LC, are shown to be required for sterile inflammatory response and survival. Finally, we showed that the stress-induced upregulation of M1-Ub chains in response to hypoxia, oxidative and mechanical stress is also induced in mammalian cells. Taken together, our results suggest that M1-Ub chains are important for NF-κB signalling in inflammation induced by stress conditions often observed in chronic inflammatory diseases and cancer.

scholarly journals The Mitochondrial Lon Protease: Novel Functions off the Beaten Track?

Biomolecules ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 253 ◽  
Author(s):  
Wolfgang Voos ◽  
Karen Pollecker
Keyword(s):  
Mammalian Cells ◽  
Protein Quality ◽  
Proteolytic Enzymes ◽  
Mitochondrial Gene ◽  
Protective Action ◽  
Stress Conditions ◽  
Endogenous Protein ◽  
The Matrix ◽  
Beaten Track ◽  
Protein Quality Control System

To maintain organellar function, mitochondria contain an elaborate endogenous protein quality control system. As one of the two soluble energy-dependent proteolytic enzymes in the matrix compartment, the protease Lon is a major component of this system, responsible for the degradation of misfolded proteins, in particular under oxidative stress conditions. Lon defects have been shown to negatively affect energy production by oxidative phosphorylation but also mitochondrial gene expression. In this review, recent studies on the role of Lon in mammalian cells, in particular on its protective action under diverse stress conditions and its relationship to important human diseases are summarized and commented.

scholarly journals Inhibition of CDKS by roscovitine suppressed LPS-induced ·NO production through inhibiting NFκB activation and BH4 biosynthesis in macrophages

2009 ◽  
Vol 297 (3) ◽  
pp. C742-C749 ◽  
Author(s):  
Jianhai Du ◽  
Na Wei ◽  
Tongju Guan ◽  
Hao Xu ◽  
Jianzhong An ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Diseases ◽  
Nuclear Factor Κb ◽  
Inhibitory Effect ◽  
Peritoneal Macrophages ◽  
Inos Mrna ◽  
No Production ◽  
Iκb Kinase ◽  
Cox 2 ◽  
Oxide Synthase

In inflammatory diseases, tissue damage is critically associated with nitric oxide (·NO) and cytokines, which are overproduced in response to cellular release of endotoxins. Here we investigated the inhibitory effect of roscovitine, a selective inhibitor of cyclin-dependent kinases (CDKs) on ·NO production in mouse macrophages. In RAW264.7 cells, we found that roscovitine abolished the production of ·NO induced by lipopolysaccharide (LPS). Moreover, roscovitine significantly inhibited LPS-induced inducible nitric oxide synthase (iNOS) mRNA and protein expression. Our data also showed that roscovitine attenuated LPS-induced phosphorylation of IκB kinase β (IKKβ), IκB, and p65 but enhanced the phosphorylation of ERK, p38, and c-Jun NH2-terminal kinase (JNK). In addition, roscovitine dose dependently inhibited LPS-induced expression of cyclooxygenase-2 (COX)-2, IL-1β, and IL-6 but not tumor necrosis factor (TNF)-α. Tetrahydrobiopterin (BH4), an essential cofactor for iNOS, is easily oxidized to 7,8-dihydrobiopterin (BH2). Roscovitine significantly inhibited LPS-induced BH4 biosynthesis and decreased BH4-to-BH2 ratio. Furthermore, roscovitine greatly reduced the upregulation of GTP cyclohydrolase-1 (GCH-1), the rate-limiting enzyme for BH4 biosynthesis. Using other CDK inhibitors, we found that CDK1, CDK5, and CDK7, but not CDK2, significantly inhibited LPS-induced ·NO production in macrophages. Similarly, in isolated peritoneal macrophages, roscovitine strongly inhibited ·NO production, iNOS, and COX-2 upregulation, activation of NFκB, and induction of GCH-1 by LPS. Together, our data indicate that roscovitine abolishes LPS-induced ·NO production in macrophages by suppressing nuclear factor-κB activation and BH4 biosynthesis, which might be mediated by CDK1, CDK5, and CDK7. Our results also suggest that roscovitine may inhibit inflammation and that CDKs may play important roles in the mechanisms by which roscovitine attenuates inflammation.

scholarly journals Annexin-A1 SUMOylation regulates microglial polarization after cerebral ischemia by modulating IKKα stability via selective autophagy

2021 ◽  
Vol 7 (4) ◽  
pp. eabc5539
Author(s):  
Xing Li ◽  
Qian Xia ◽  
Meng Mao ◽  
Huijuan Zhou ◽  
Lu Zheng ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Annexin A1 ◽  
Selective Autophagy ◽  
Microglial Polarization ◽  
Proinflammatory Mediators ◽  
Therapeutic Benefits ◽  
Iκb Kinase ◽  
Ikk Complex

Annexin-A1 (ANXA1) has recently been proposed to play a role in microglial activation after brain ischemia, but the underlying mechanism remains poorly understood. Here, we demonstrated that ANXA1 is modified by SUMOylation, and SUMOylated ANXA1 could promote the beneficial phenotype polarization of microglia. Mechanistically, SUMOylated ANXA1 suppressed nuclear factor κB activation and the production of proinflammatory mediators. Further study revealed that SUMOylated ANXA1 targeted the IκB kinase (IKK) complex and selectively enhanced IKKα degradation. Simultaneously, we detected that SUMOylated ANXA1 facilitated the interaction between IKKα and NBR1 to promote IKKα degradation through selective autophagy. Further work revealed that the overexpression of SUMOylated ANXA1 in microglia/macrophages resulted in marked improvement in neurological function in a mouse model of cerebral ischemia. Collectively, our study demonstrates a previously unidentified mechanism whereby SUMOylated ANXA1 regulates microglial polarization and strongly indicates that up-regulation of ANXA1 SUMOylation in microglia may provide therapeutic benefits for cerebral ischemia.

A manganese oxide nanozyme prevents the oxidative damage of biomolecules without affecting the endogenous antioxidant system

Nanoscale ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 3855-3863 ◽  
Author(s):  
Namrata Singh ◽  
Mohammed Azharuddin Savanur ◽  
Shubhi Srivastava ◽  
Patrick D'Silva ◽  
Govindasamy Mugesh
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Manganese Oxide ◽  
Antioxidant System ◽  
Mammalian Cells ◽  
Redox State ◽  
Stress Conditions ◽  
System P ◽  
Endogenous Antioxidant ◽  
Antioxidant Machinery

Multi-enzyme mimetic Mn3O4 nanoflowers (Mp) modulate the redox state of mammalian cells without altering the cellular antioxidant machinery under oxidative stress conditions.

scholarly journals “Re-educating” tumor-associated macrophages by targeting NF-κB

2008 ◽  
Vol 205 (6) ◽  
pp. 1261-1268 ◽  
Author(s):  
Thorsten Hagemann ◽  
Toby Lawrence ◽  
Iain McNeish ◽  
Kellie A. Charles ◽  
Hagen Kulbe ◽  
...  
Keyword(s):  
Nk Cell ◽  
Nuclear Factor Κb ◽  
Tumor Associated Macrophages ◽  
Tumoricidal Activity ◽  
Macrophage Population ◽  
Cell Recruitment ◽  
Histocompatibility Complex ◽  
Iκb Kinase ◽  
Classically Activated

The nuclear factor κB (NF-κB) signaling pathway is important in cancer-related inflammation and malignant progression. Here, we describe a new role for NF-κB in cancer in maintaining the immunosuppressive phenotype of tumor-associated macrophages (TAMs). We show that macrophages are polarized via interleukin (IL)-1R and MyD88 to an immunosuppressive “alternative” phenotype that requires IκB kinase β–mediated NF-κB activation. When NF-κB signaling is inhibited specifically in TAMs, they become cytotoxic to tumor cells and switch to a “classically” activated phenotype; IL-12high, major histocompatibility complex IIhigh, but IL-10low and arginase-1low. Targeting NF-κB signaling in TAMs also promotes regression of advanced tumors in vivo by induction of macrophage tumoricidal activity and activation of antitumor activity through IL-12–dependent NK cell recruitment. We provide a rationale for manipulating the phenotype of the abundant macrophage population already located within the tumor microenvironment; the potential to “re-educate” the tumor-promoting macrophage population may prove an effective and novel therapeutic approach for cancer that complements existing therapies.

scholarly journals Immunoglobulin light chains activate nuclear factor-κB in renal epithelial cells through a Src-dependent mechanism

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1301-1307 ◽  
Author(s):  
Wei-Zhong Ying ◽  
Pei-Xuan Wang ◽  
Kristal J. Aaron ◽  
Kolitha Basnayake ◽  
Paul W. Sanders
Keyword(s):  
Epithelial Cells ◽  
Tyrosine Phosphorylation ◽  
Renal Injury ◽  
Src Kinase ◽  
Nuclear Factor Κb ◽  
Light Chains ◽  
Nuclear Factor ◽  
Monocyte Chemoattractant Protein 1 ◽  
Renal Epithelial Cells ◽  
Iκb Kinase

Abstract One of the major attendant complications of multiple myeloma is renal injury, which contributes significantly to morbidity and mortality in this disease. Monoclonal immunoglobulin free light chains (FLCs) are usually directly involved, and tubulointerstitial renal injury and fibrosis are prominent histologic features observed in myeloma. The present study examined the role of monoclonal FLCs in altering the nuclear factor κ light chain enhancer of activated B cells (NF-κB) activity of renal epithelial cells. Human proximal tubule epithelial cells exposed to 3 different human monoclonal FLCs demonstrated Src kinase–dependent activation of the NF-κB pathway, which increased production of monocyte chemoattractant protein-1 (MCP-1). Tyrosine phosphorylation of inhibitor of κB kinases (IKKs) IKKα and IKKβ and a concomitant increase in inhibitor of κB (IκB) kinase activity in cell lysates were observed. Time-dependent, Src kinase–dependent increases in serine and tyrosine phosphorylation of IκBα and NF-κB activity were also demonstrated. Proteasome inhibition partially blocked FLC-induced MCP-1 production. These findings fit into a paradigm characterized by FLC-induced redox-signaling events that activated the canonical and atypical (IKK-independent) NF-κB pathways to promote a proinflammatory, profibrotic renal environment.

scholarly journals Oxidative Stress Transiently Decreases the IKK Complex (IKKα, β, and γ), an Upstream Component of NF-κB Signaling, after Transient Focal Cerebral Ischemia in Mice

2005 ◽  
Vol 25 (10) ◽  
pp. 1301-1311 ◽  
Author(s):  
Yun S Song ◽  
Yong-Sun Lee ◽  
Pak H Chan
Keyword(s):  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Dna Array ◽  
Wild Type ◽  
Iκb Kinase ◽  
Transient Focal Cerebral Ischemia ◽  
Ikk Complex ◽  
In The Wild

Nuclear factor-κB (NF-κB) has a central role in coordinating the expression of a wide variety of genes that control cerebral ischemia. Although there has been intense research on NF-κB, its mechanisms in the ischemic brain have not been clearly elucidated. We investigated the temporal profile of NF-κB-related genes using a complementary DNA array method in wild-type mice and human copper/zinc-superoxide dismutase transgenic (SOD1 Tg) mice that had low-level reactive oxygen species (ROS) by scavenging superoxide. Our DNA array showed that IκB kinase (IKK) complex (IKKα, β, and γ) mRNA in the wild-type mice was decreased as early as 1 h after reperfusion, after 30 mins of transient focal cerebral ischemia (tFCI). In contrast, tFCI in the SOD1 Tg mice caused an increase in the IKK complex. The IKK complex protein levels were also drastically decreased at 1 h in the wild-type mice, but did not change in the SOD1 Tg mice throughout the 7 days. Electrophoretic mobility shift assay revealed activation of NF-κB DNA binding after tFCI in the wild-type mice. Nuclear factor-κB activation occurred at the same time, as did the phosphorylation and degradation of the inhibitory protein κBα. However, SOD1 prevented NF-κB activation, and phosphorylation and degradation of IκBα after tFCI. Superoxide production and ubiquitinated protein in the SOD1 Tg mice were also lower than in the wild-type mice after tFCI. These results suggest that ROS are implicated in transient downregulation of IKKα, β, and γ in cerebral ischemia.

Monitoring spatial and temporal metabolic dynamics of woody poplar root under mechanical stress conditions by NMR-based metabolomics

Metabolomics ◽  
2016 ◽  
Vol 12 (4) ◽  
Author(s):  
Gabriella Saviano ◽  
Debora Paris ◽  
Dominique Melck ◽  
Antonio Falasca ◽  
Dalila Trupiano ◽  
...  
Keyword(s):  
Mechanical Stress ◽  
Stress Conditions ◽  
Poplar Root

scholarly journals Cell-specific Activation of Nuclear Factor-κB by the ParasiteTrypanosoma cruziPromotes Resistance to Intracellular Infection

2000 ◽  
Vol 11 (1) ◽  
pp. 153-160 ◽  
Author(s):  
Belinda S. Hall ◽  
Winnie Tam ◽  
Ranjan Sen ◽  
Miercio E. A. Pereira
Keyword(s):  
Mammalian Cells ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Microbial Pathogens ◽  
Tissue Tropism ◽  
Nuclear Factor ◽  
Infection Level ◽  
Direct Role ◽  
Intracellular Infection

The transcription factor nuclear factor-κB (NF-κB) is central to the innate and acquired immune response to microbial pathogens, coordinating cellular responses to the presence of infection. Here we demonstrate a direct role for NF-κB activation in controlling intracellular infection in nonimmune cells. Trypanosoma cruzi is an intracellular parasite of mammalian cells with a marked preference for infection of myocytes. The molecular basis for this tissue tropism is unknown. Trypomastigotes, the infectious stage of T. cruzi, activate nuclear translocation and DNA binding of NF-κB p65 subunit and NF-κB-dependent gene expression in epithelial cells, endothelial cells, and fibroblasts. Inactivation of epithelial cell NF-κB signaling by inducible expression of the inhibitory mutant IκBaM significantly enhances parasite invasion.T. cruzi do not activate NF-κB in cells derived from skeletal, smooth, or cardiac muscle, despite the ability of these cells to respond to tumor necrosis factor-α with NF-κB activation. The in vitro infection level in these muscle-derived cells is more than double that seen in the other cell types tested. Therefore, the ability of T. cruzi to activate NF-κB correlates inversely with susceptibility to infection, suggesting that NF-κB activation is a determinant of the intracellular survival and tissue tropism ofT. cruzi.

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