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.

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.

scholarly journals Oxidative Stress Increases Phosphorylation of IκB Kinase-α by Enhancing NF-κB-Inducing Kinase after Transient Focal Cerebral Ischemia

2010 ◽  
Vol 30 (7) ◽  
pp. 1265-1274 ◽  
Author(s):  
Yun Seon Song ◽  
Min-Soo Kim ◽  
Hyun-Ae Kim ◽  
Bo-In Jung ◽  
Jiwon Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Nuclear Factor Κb ◽  
Nuclear Accumulation ◽  
Brain Endothelial Cells ◽  
Iκb Kinase ◽  
Transient Focal Cerebral Ischemia ◽  
Mouse Brain Endothelial Cells

The IκB kinase (IKK) complex is a central component in the classic activation of the nuclear factor-κB (NF-κB) pathway. It has been reported to function in physiologic responses, including cell death and inflammation. We have shown that IKK is regulated by oxidative status after transient focal cerebral ischemia (tFCI) in mice. However, the mechanism by which oxidative stress influences IKKs after tFCI is largely unknown. Nuclear accumulation and phosphorylation of IKKα (pIKKα) were observed 1 h after 30 mins of tFCI in mice. In copper/zinc-superoxide dismutase knockout mice, levels of NF-κB-inducing kinase (NIK) (an upstream kinase of IKKα), pIKKα, and phosphorylation of histone H3 (pH3) on Ser10 were increased after tFCI and were higher than in wild-type mice. Immunohistochemistry showed nuclear accumulation and pIKKα in mouse brain endothelial cells after tFCI. Nuclear factor-κB-inducing kinase was increased, and it enhanced pH3 by inducing pIKKα after oxygen–glucose deprivation (OGD) in mouse brain endothelial cells. Both NIK and pH3 interactions with IKKα were confirmed by coimmunoprecipitation. Treatment with IKKα small interfering RNA significantly reduced cell death after OGD. These results suggest that augmentation of NIK, IKKα, and pH3 in response to oxidative stress is involved in cell death after cerebral ischemia (or stroke).

Resveratrol promotes recovery of immune function of immunosuppressive mice by activating JNK/NF-κB pathway in splenic lymphocytes

2017 ◽  
Vol 95 (6) ◽  
pp. 763-767 ◽  
Author(s):  
Xin Lai ◽  
Mei Cao ◽  
Xu Song ◽  
Renyong Jia ◽  
Yuanfeng Zou ◽  
...  
Keyword(s):  
Natural Compound ◽  
Underlying Mechanism ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Spleen Lymphocyte ◽  
Splenic Lymphocytes ◽  
Jnk Pathway ◽  
Immunologic Function ◽  
Iκb Kinase ◽  
Regulatory Effects

Resveratrol, a natural compound found in over 70 plants, is known to possess immunoregulatory effects and anti-inflammatory activity. It has been shown that resveratrol has regulatory effects on different signaling pathways in different diseases. However, few reports have evaluated the effects of resveratrol on reinforcing immunity recovery via activating nuclear factor-κB (NF-κB) pathway and Jun N-terminal kinases (JNK) pathway. The present study aimed to assess immune-enhancing activity and underlying mechanism of resveratrol in immunosuppressive mice. Previously, we reported that resveratrol could promote mouse spleen lymphocyte functions to recover the immune system effectively. In the present study, we show that resveratrol could upregulate the expressions of NF-κB, IκB kinase, JNK, and c-jun in splenic lymphocytes of immunosuppressive mice. Taken together, our results indicate that resveratrol could promote recovery of immunologic function in immunosuppressive mice by activating JNK/NF-κB pathway.

scholarly journals Myosin motor Myo1c and its receptor NEMO/IKK-γ promote TNF-α–induced serine307 phosphorylation of IRS-1

2006 ◽  
Vol 173 (5) ◽  
pp. 665-671 ◽  
Author(s):  
Yoshitaka Nakamori ◽  
Masahiro Emoto ◽  
Naofumi Fukuda ◽  
Akihiko Taguchi ◽  
Shigeru Okuya ◽  
...  
Keyword(s):  
Motor Protein ◽  
Nuclear Factor Κb ◽  
Receptor Protein ◽  
Cytoskeletal Network ◽  
Iκb Kinase ◽  
Tnf Α ◽  
Ikk Complex ◽  
Factor Α ◽  
And Function ◽  
Necrosis Factor

Tumor necrosis factor-α (TNF-α) signaling through the IκB kinase (IKK) complex attenuates insulin action via the phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser307. However, the precise molecular mechanism by which the IKK complex phosphorylates IRS-1 is unknown. In this study, we report nuclear factor κB essential modulator (NEMO)/IKK-γ subunit accumulation in membrane ruffles followed by an interaction with IRS-1. This intracellular trafficking of NEMO requires insulin, an intact actin cytoskeletal network, and the motor protein Myo1c. Increased Myo1c expression enhanced the NEMO–IRS-1 interaction, which is essential for TNF-α– induced phosphorylation of Ser307–IRS-1. In contrast, dominant inhibitory Myo1c cargo domain expression diminished this interaction and inhibited IRS-1 phosphorylation. NEMO expression also enhanced TNF-α–induced Ser307–IRS-1 phosphorylation and inhibited glucose uptake. In contrast, a deletion mutant of NEMO lacking the IKK-β–binding domain or silencing NEMO blocked the TNF-α signal. Thus, motor protein Myo1c and its receptor protein NEMO act cooperatively to form the IKK–IRS-1 complex and function in TNF-α–induced insulin resistance.

scholarly journals The IKKβ Subunit of IκB Kinase (IKK) is Essential for Nuclear Factor κB Activation and Prevention of Apoptosis

1999 ◽  
Vol 189 (11) ◽  
pp. 1839-1845 ◽  
Author(s):  
Zhi-Wei Li ◽  
Wenming Chu ◽  
Yinling Hu ◽  
Mireille Delhase ◽  
Tom Deerinck ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Regulatory Subunit ◽  
Nuclear Factor ◽  
Catalytic Subunits ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Factor Α ◽  
Necrosis Factor

The IκB kinase (IKK) complex is composed of three subunits, IKKα, IKKβ, and IKKγ (NEMO). While IKKα and IKKβ are highly similar catalytic subunits, both capable of IκB phosphorylation in vitro, IKKγ is a regulatory subunit. Previous biochemical and genetic analyses have indicated that despite their similar structures and in vitro kinase activities, IKKα and IKKβ have distinct functions. Surprisingly, disruption of the Ikkα locus did not abolish activation of IKK by proinflammatory stimuli and resulted in only a small decrease in nuclear factor (NF)-κB activation. Now we describe the pathophysiological consequence of disruption of the Ikkβ locus. IKKβ-deficient mice die at mid-gestation from uncontrolled liver apoptosis, a phenotype that is remarkably similar to that of mice deficient in both the RelA (p65) and NF-κB1 (p50/p105) subunits of NF-κB. Accordingly, IKKβ-deficient cells are defective in activation of IKK and NF-κB in response to either tumor necrosis factor α or interleukin 1. Thus IKKβ, but not IKKα, plays the major role in IKK activation and induction of NF-κB activity. In the absence of IKKβ, IKKα is unresponsive to IKK activators.

scholarly journals The Physiological functions of IKK-selective substrate identification and their critical roles in diseases

STEMedicine ◽  
2020 ◽  
Vol 1 (4) ◽  
pp. e49 ◽  
Author(s):  
Jian-shuai Yu ◽  
Jin Jin ◽  
Yi-yuan Li
Keyword(s):  
Structural Biology ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Biomedical Science ◽  
Nuclear Factor ◽  
The Core ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Main Regulator

The nuclear factor κB (NF-κB) transcription factors exert central hub functions in multiple physiologicalprocesses including immune response, cell survival, proliferation and cytokine production, which hasnaturally become the core of research almost in all aspects of biomedical science over 30 years. Sinceboth the activation and termination of NF-κB pathway are tightly regulated, little alteration can lead toexcessive inflammatory responses and even result in tissue damage and severe diseases. The inhibitor ofnuclear factor kappa-B (IκB) kinase (IKK) complex is the main regulator of the NF-κB signaling pathway,they mediate and deliver signals through phosphorylating certain substrates. In recent years, increasedproteins have been identified to be targeted by IKK members and the particular modification mechanismbecomes clear with the development of detecting techniques and structural biology. In this review, wesummarize the known substrates of IKK family members either relevant or irrelevant to NF-κB signaling,their structures and phosphorylation patterns, and the related physiologic and/or pathologic responses.Understanding the regulation of IKKs on their substrates may be helpful to connect IKKs with specificsignaling pathways or physiological phenomena, and is essential for targeting IKKs in clinical research.

scholarly journals TNF and IL-1 exhibit distinct ubiquitin requirements for inducing NEMO–IKK supramolecular structures

2014 ◽  
Vol 204 (2) ◽  
pp. 231-245 ◽  
Author(s):  
Nadine Tarantino ◽  
Jean-Yves Tinevez ◽  
Elizabeth Faris Crowell ◽  
Bertrand Boisson ◽  
Ricardo Henriques ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Supramolecular Complexes ◽  
Cell Periphery ◽  
Nuclear Factor ◽  
Tnf Receptors ◽  
Ubiquitin Chain ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Order Complexes

Nuclear factor κB (NF-κB) essential modulator (NEMO), a regulatory component of the IκB kinase (IKK) complex, controls NF-κB activation through its interaction with ubiquitin chains. We show here that stimulation with interleukin-1 (IL-1) and TNF induces a rapid and transient recruitment of NEMO into punctate structures that are anchored at the cell periphery. These structures are enriched in activated IKK kinases and ubiquitinated NEMO molecules, which suggests that they serve as organizing centers for the activation of NF-κB. These NEMO-containing structures colocalize with activated TNF receptors but not with activated IL-1 receptors. We investigated the involvement of nondegradative ubiquitination in the formation of these structures, using cells deficient in K63 ubiquitin chains or linear ubiquitin chain assembly complex (LUBAC)-mediated linear ubiquitination. Our results indicate that, unlike TNF, IL-1 requires K63-linked and linear ubiquitin chains to recruit NEMO into higher-order complexes. Thus, different mechanisms are involved in the recruitment of NEMO into supramolecular complexes, which appear to be essential for NF-κB activation.

scholarly journals Autophagic feedback-mediated degradation of IKKα requires CHK1- and p300/CBP-dependent acetylation of p53

2020 ◽  
Vol 133 (22) ◽  
pp. jcs246868
Author(s):  
Xiuduan Xu ◽  
Chongchong Zhang ◽  
Huan Xu ◽  
Lin Wu ◽  
Meiru Hu ◽  
...  
Keyword(s):  
Complex Formation ◽  
Feedback Loop ◽  
Hepatoma Cell ◽  
Critical Role ◽  
Human Hepatoma Cells ◽  
Catalytic Subunits ◽  
Selective Autophagy ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Autophagic Degradation

ABSTRACTIn our previous report, we demonstrated that one of the catalytic subunits of the IκB kinase (IKK) complex, IKKα (encoded by CHUK), performs an NF-κB-independent cytoprotective role in human hepatoma cells under the treatment of the anti-tumor therapeutic reagent arsenite. IKKα triggers its own degradation, as a feedback loop, by activating p53-dependent autophagy, and therefore contributes substantially to hepatoma cell apoptosis induced by arsenite. Interestingly, IKKα is unable to interact with p53 directly but plays a critical role in mediating p53 phosphorylation (at Ser15) by promoting CHK1 activation and CHK1–p53 complex formation. In the current study, we found that p53 acetylation (at Lys373 and/or Lys382) was also critical for the induction of autophagy and the autophagic degradation of IKKα during the arsenite response. Furthermore, IKKα was involved in p53 acetylation through interaction with the acetyltransferases for p53, p300 (also known as EP300) and CBP (also known as CREBBP) (collectively p300/CBP), inducing CHK1-dependent p300/CBP activation and promoting p300–p53 or CBP–p53 complex formation. Therefore, taken together with the previous report, we conclude that both IKKα- and CHK1-dependent p53 phosphorylation and acetylation contribute to mediating selective autophagy feedback degradation of IKKα during the arsenite-induced proapoptotic responses.

scholarly journals The c-FLIP–NH2 terminus (p22-FLIP) induces NF-κB activation

2006 ◽  
Vol 203 (5) ◽  
pp. 1295-1305 ◽  
Author(s):  
Alexander Golks ◽  
Dirk Brenner ◽  
Peter H. Krammer ◽  
Inna N. Lavrik
Keyword(s):  
Essential Role ◽  
Death Receptor ◽  
Nuclear Factor Κb ◽  
Cleavage Product ◽  
Nuclear Factor ◽  
T And B Cells ◽  
Signaling Complex ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Induced Apoptosis

c-FLIP proteins (isoforms: c-FLIPL, c-FLIPS, and c-FLIPR) play an essential role in the regulation of death receptor–induced apoptosis. Here, we demonstrate that the cytoplasmic NH2-terminal procaspase-8 cleavage product of c-FLIP (p22-FLIP) found in nonapoptotic malignant cells, primary T and B cells, and mature dendritic cells (DCs) strongly induces nuclear factor κB (NF-κB) activity by interacting with the IκB kinase (IKK) complex via the IKKγ subunit. Thus, in addition to inhibiting apoptosis by binding to the death-inducing signaling complex, our data demonstrate a novel mechanism by which c-FLIP controls NF-κB activation and life/death decisions in lymphocytes and DCs.

Helicobacter pylori-induced tyrosine phosphorylation of IKKβ contributes to NF-κB activation

2011 ◽  
Vol 392 (4) ◽  
Author(s):  
Cornelia Rieke ◽  
Anja Papendieck ◽  
Olga Sokolova ◽  
Michael Naumann
Keyword(s):  
Helicobacter Pylori ◽  
Tyrosine Phosphorylation ◽  
Nuclear Factor Κb ◽  
Gastric Diseases ◽  
Catalytic Subunits ◽  
Proinflammatory Mediators ◽  
Iκb Kinase ◽  
Infected Cells ◽  
H Pylori ◽  
Interfering Rna

Abstract Helicobacter pylori, the etiological agent of several human gastric diseases, induces the transcription factor nuclear factor-κB (NF-κB) in colonized epithelial cells leading to the release of proinflammatory mediators. Activation of NF-κB involves the IκB kinase (IKK)-complex composed of two catalytic subunits, IKKα and IKKβ, and a regulatory scaffold protein, IKKγ. IKKβ was shown to be essential for NF-κB activation in response to a variety of stimuli including H. pylori. In addition to the phosphorylation of serine residues, tyrosine phosphorylation could be crucial for IKKβ activation. Here we provide evidence that IKKβ phosphorylation is induced in lipid rafts (DRM fractions) of H. pylori-infected cells, but not TNFα-stimulated cells. Furthermore, H. pylori transiently induces binding of IKKβ to c-Src kinase. Inhibition of c-Src by specific inhibitors as well as knockdown of c-Src by small interfering RNA reduced phosphorylation of IκBα as well as of p65. Thus, tyrosine-phosphorylated IKKβ contributes at least in part to NF-κB activation in response to H. pylori infection.

Sign in / Sign up

Export Citation Format

Share Document