Adaptor Protein-3–Mediated Trafficking of TLR2 Ligands Controls Specificity of Inflammatory Responses but Not Adaptor Complex Assembly

The adaptor protein Vinexin-β exacerbates MI-induced heart damage through aggravating the inflammatory and apoptotic responses dependent on inactivation of Akt signalling.

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Co-expression of Mitochondrial Genes and ACE2 in Cornea Involved in COVID-19 Infection

10.1101/2020.07.23.216770 ◽

2020 ◽

Author(s):

Jian Yuan ◽

Dandan Fan ◽

Zhengbo Xue ◽

Jia Qu ◽

Jianzhong Su

Keyword(s):

Mitochondrial Function ◽

Inflammatory Responses ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Adaptor Protein ◽

Interaction Network ◽

Mitochondrial Genes ◽

Host Susceptibility ◽

Therapeutic Interventions ◽

Significant Enrichment

AbstractThe Coronavirus disease 2019 (COVID-19) pandemic severely challenges public health and necessitates the need for increasing our understanding of COVID-19 pathogenesis, especially host factors facilitating virus infection and propagation. Here, the co-expression network was constructed by mapping the well-known ACE2, TMPRSS2 and host susceptibility genes implicated in COVID-19 GWAS onto a cornea, retinal pigment epithelium and lung. We found a significant co-expression module of these genes in the cornea, revealing that cornea is potential extra-respiratory entry portal of SARS-CoV-2. Strikingly, both co-expression and interaction networks show a significant enrichment in mitochondrial function, which are the hub of cellular oxidative homeostasis, inflammation and innate immune response. We identified a corneal mitochondrial susceptibility module (CMSM) of 14 mitochondrial genes by integrating ACE2 co-expression cluster and SARS-CoV-2 interactome. Gene ECSIT, as a cytosolic adaptor protein involved in inflammatory responses, exhibits the strongest correlation with ACE2 in CMSM, which has shown to be an important risk factor for SARS-CoV-2 infection and prognosis. Our co-expression and protein interaction network analysis uncover that the mitochondrial function related genes in cornea contribute to the dissection of COVID-19 susceptibility and potential therapeutic interventions.

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Haemophilus influenzae Porin Induces Toll-Like Receptor 2-Mediated Cytokine Production in Human Monocytes and Mouse Macrophages

Infection and Immunity ◽

10.1128/iai.72.2.1204-1209.2004 ◽

2004 ◽

Vol 72 (2) ◽

pp. 1204-1209 ◽

Cited By ~ 51

Author(s):

Marilena Galdiero ◽

Massimiliano Galdiero ◽

Emiliana Finamore ◽

Fabio Rossano ◽

Maria Gambuzza ◽

...

Keyword(s):

Haemophilus Influenzae ◽

Cytokine Production ◽

Inflammatory Responses ◽

Adaptor Protein ◽

Monocytic Cell ◽

Monocytic Cell Line ◽

Necrosis Factor Alpha ◽

Human Monocytic Cell Line ◽

Tnf Α ◽

Human Monocytic Cell

ABSTRACT The production of proinflammatory cytokines is likely to play a major pathophysiological role in meningitis and other infections caused by Haemophilus influenzae type b (Hib). Previous studies have shown that Hib porin contributes to signaling of the inflammatory cascade. We examined here the role of Toll-like receptors (TLRs) and the TLR-associated adaptor protein MyD88 in Hib porin-induced production of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Hib porin-induced TNF-α and IL-6 production was virtually eliminated in macrophages from TLR2- or MyD88-deficient mice. In contrast, macrophages from lipopolysaccharide (LPS)-hyporesponsive C3H/HeJ mice, which are defective in TLR4 function, responded normally to Hib porin. Moreover anti-TLR2 antibodies but not anti-TLR4 antibodies significantly reduced Hib porin-stimulated TNF-α and IL-6 release from the human monocytic cell line THP-1. These data indicate that the TLR2/MyD88 pathway plays an essential role in Hib porin-mediated cytokine production. These findings may be useful in the development of alternative therapies aimed at reducing excessive inflammatory responses during Hib infections.

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CaMKII promotes TLR-triggered proinflammatory cytokine and type I interferon production by directly binding and activating TAK1 and IRF3 in macrophages

Blood ◽

10.1182/blood-2008-03-144022 ◽

2008 ◽

Vol 112 (13) ◽

pp. 4961-4970 ◽

Cited By ~ 121

Author(s):

Xingguang Liu ◽

Ming Yao ◽

Nan Li ◽

Chunmei Wang ◽

Yuanyuan Zheng ◽

...

Keyword(s):

Protein Kinase ◽

Intracellular Calcium ◽

Calcium Release ◽

Transforming Growth Factor ◽

Inflammatory Responses ◽

Adaptor Protein ◽

Mitogen Activated Protein Kinase ◽

Interferon Α ◽

Type I ◽

Tlr Signaling

Abstract Calcium and its major downstream effector, calcium/calmodulin-dependent protein kinase II (CaMKII), are found to be important for the functions of immune cells. Lipopolysaccharide (LPS) has been shown to induce intracellular calcium release in macrophages; however, whether and how CaMKII is required for Toll-like receptor (TLR) signaling remain unknown. Here we demonstrate that TLR 4, 9, and 3 ligands markedly induce intracellular calcium fluxes and activate CaMKII-α in macrophages. Selective inhibition or RNA interference of CaMKII significantly suppresses TLR4, 9, 3-triggered production of interleukin-6 (IL-6), tumor necrosis factor-α, and interferon-α/β (IFN-α/β) in macrophages. Coincidently, overexpression of constitutively active CaMKII-α significantly enhances production of the above cytokines. In addition to the activation of mitogen-activated protein kinase and nuclear factor κB pathways, CaMKII-α can directly bind and phosphorylate transforming growth factor β–activated kinase 1 (TAK1) and IFN regulatory factor 3 (IRF3; serine on 386) via the N-terminal part of its regulatory domain. Therefore, CaMKII can be activated by TLR ligands, and in turn promotes both myeloid differentiating factor 88 and Toll/IL-1 receptor domain-containing adaptor protein-inducing IFN-β–dependent inflammatory responses by directly activating TAK1 and IRF3. The cross-talk with the calcium/CaMKII pathway is needed for full activation of TLR signaling in macrophages.

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The PAAD/PYRIN-Family Protein ASC Is a Dual Regulator of a Conserved Step in Nuclear Factor κB Activation Pathways

Journal of Experimental Medicine ◽

10.1084/jem.20021552 ◽

2002 ◽

Vol 196 (12) ◽

pp. 1605-1615 ◽

Cited By ~ 116

Author(s):

Christian Stehlik ◽

Loredana Fiorentino ◽

Andrea Dorfleutner ◽

Jean-Marie Bruey ◽

Eugenia M. Ariza ◽

...

Keyword(s):

Inflammatory Responses ◽

Adaptor Protein ◽

Large Family ◽

Nuclear Factor Κb ◽

Inhibitory Influence ◽

Nuclear Factor ◽

Death Domain ◽

Protein Levels ◽

Inflammatory Stimuli ◽

Activation Pathways

Apoptosis-associated speck-like protein containing a Caspase recruitment domain (ASC) belongs to a large family of proteins that contain a Pyrin, AIM, ASC, and death domain-like (PAAD) domain (also known as PYRIN, DAPIN, Pyk). Recent data have suggested that ASC functions as an adaptor protein linking various PAAD-family proteins to pathways involved in nuclear factor (NF)-κB and pro-Caspase-1 activation. We present evidence here that the role of ASC in modulating NF-κB activation pathways is much broader than previously suspected, as it can either inhibit or activate NF-κB, depending on cellular context. While coexpression of ASC with certain PAAD-family proteins such as Pyrin and Cryopyrin increases NF-κB activity, ASC has an inhibitory influence on NF-κB activation by various proinflammatory stimuli, including tumor necrosis factor (TNF)α, interleukin 1β, and lipopolysaccharide (LPS). Elevations in ASC protein levels or of the PAAD domain of ASC suppressed activation of IκB kinases in cells exposed to pro-inflammatory stimuli. Conversely, reducing endogenous levels of ASC using siRNA enhanced TNF- and LPS-induced degradation of the IKK substrate, IκBα. Our findings suggest that ASC modulates diverse NF-κB induction pathways by acting upon the IKK complex, implying a broad role for this and similar proteins containing PAAD domains in regulation of inflammatory responses.

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O-40 Lenalidomide inhibits proliferation of chromosome 5 mutant hematopoietic tumor cells and interferes with adaptor protein complex assembly and phosphorylation

Leukemia Research ◽

10.1016/s0145-2126(05)80038-4 ◽

2005 ◽

Vol 29 ◽

pp. S14

Author(s):

A. Krithivas Gandhi ◽

P.H. Schafer ◽

S. Naziruddin ◽

A. Parton ◽

D. Verhelle ◽

...

Keyword(s):

Tumor Cells ◽

Protein Complex ◽

Adaptor Protein ◽

Chromosome 5 ◽

Complex Assembly ◽

Protein Complex Assembly

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Neutrophils require SKAP2 for reactive oxygen species production following C-type lectin and Candida stimulation

10.1101/2021.03.02.433609 ◽

2021 ◽

Author(s):

Giang T. Nguyen ◽

Shuying Xu ◽

Stephen C. Bunnell ◽

Michael K. Mansour ◽

David B. Sykes ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Host Defense ◽

Yersinia Pseudotuberculosis ◽

Inflammatory Responses ◽

Reactive Oxygen ◽

Adaptor Protein ◽

Cellular Adhesion ◽

Ros Generation ◽

Oxygen Species ◽

Lectin Receptors

AbstractSignaling cascades that convert the recognition of pathogens to efficient inflammatory responses by immune cells, specifically neutrophils, are critical for host survival. SKAP2, an adaptor protein, is required for reactive oxygen species (ROS) generation following stimulation by integrins, formyl peptide receptors and gram-negative bacteria Klebsiella pneumoniae and Yersinia pseudotuberculosis in vitro (Nguyen et al., 2020, Shaban et al., 2020, Boras et al., 2017). SKAP2 is also required for the host defense against K. pneumoniae and ΔyopH Y. pseudotuberculosis infection in vivo in mouse models (Shaban et al., 2020, Nguyen et al., 2020). Another class of pattern recognition receptors (PRR) is the C-type lectin receptors (CLR), such as Dectin-1, Dectin-2 and Mincle, that are critical to trigger innate immune responses. Using neutrophils from murine HoxB8-immortalized progenitors, we show that SKAP2 is crucial for maximal ROS response to purified CLR agonists and to the fungal pathogens Candida glabrata and C. albicans, as well as for robust killing of C. glabrata. Skap2-/- murine neutrophils failed to generate ROS and exhibited reduced cellular adhesion in response to trehalose-6,6’-dibehenate (TDB), furfurman, and curdlan, Mincle, Dectin-2, and Dectin-1 agonists, respectively. TDB, furfurman, and curdlan stimulation also led to SKAP2-independent integrin conformational changes, showing that inside-out signaling by these CLRs to integrin occurs in the absence of SKAP2. Pyk2 phosphorylation was significantly reduced after infection with C. glabrata in Skap2-/- neutrophils, while Syk phosphorylation was unaffected by the loss of SKAP2. These data strengthen the importance of SKAP2 in the activation of neutrophil ROS production by PRRs to include CLRs and extend the role of SKAP2 in host defense beyond antibacterial immunity to include Candida species.

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Critical Role for MyD88-Mediated Neutrophil Recruitment during Clostridium difficile Colitis

Infection and Immunity ◽

10.1128/iai.00448-12 ◽

2012 ◽

Vol 80 (9) ◽

pp. 2989-2996 ◽

Cited By ~ 92

Author(s):

Irene Jarchum ◽

Mingyu Liu ◽

Chao Shi ◽

Michele Equinda ◽

Eric G. Pamer

Keyword(s):

Clostridium Difficile ◽

Inflammatory Responses ◽

Adaptor Protein ◽

Neutrophil Recruitment ◽

Innate Immune ◽

Antibiotic Administration ◽

Immune Signaling ◽

Content Type ◽

Innate Immune Signaling ◽

Deficient Mice

ABSTRACTClostridium difficilecan infect the large intestine and cause colitis when the normal intestinal microbiota is altered by antibiotic administration. Little is known about the innate immune signaling pathways that marshal inflammatory responses toC. difficileinfection and whether protective and pathogenic inflammatory responses can be dissociated. Toll-like receptors predominantly signal via the MyD88 adaptor protein and are important mediators of innate immune signaling in the intestinal mucosa. Here, we demonstrate that MyD88-mediated signals trigger neutrophil and CCR2-dependent Ly6Chimonocyte recruitment to the colonic lamina propria (cLP) during infection, which prevent dissemination of bystander bacteria to deeper tissues. Mortality is markedly increased in MyD88-deficient mice followingC. difficileinfection, as are parameters of mucosal tissue damage and inflammation. Antibody-mediated depletion of neutrophils markedly increases mortality, while attenuated recruitment of Ly6Chimonocytes in CCR2-deficient mice does not alter the course ofC. difficileinfection. Expression of CXCL1, a neutrophil-recruiting chemokine, is impaired in the cLP of MyD88−/−mice. Our studies suggest that MyD88-mediated signals promote neutrophil recruitment by inducing expression of CXCL1, thereby providing critical early defense againstC. difficile-mediated colitis.

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Lenalidomide inhibits proliferation of Namalwa CSN.70 cells and interferes with Gab1 phosphorylation and adaptor protein complex assembly

Leukemia Research ◽

10.1016/j.leukres.2006.01.010 ◽

2006 ◽

Vol 30 (7) ◽

pp. 849-858 ◽

Cited By ~ 64

Author(s):

Anita K. Gandhi ◽

Jian Kang ◽

Syedah Naziruddin ◽

Anastasia Parton ◽

Peter H. Schafer ◽

...

Keyword(s):

Protein Complex ◽

Adaptor Protein ◽

Complex Assembly ◽

Protein Complex Assembly

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Directionality of PYD filament growth determined by the transition of NLRP3 nucleation seeds to ASC elongation

10.1101/2021.11.25.470035 ◽

2021 ◽

Author(s):

Inga V. Hochheiser ◽

Heide Behrmann ◽

Gregor Hagelueken ◽

Juan F. Rodriguez-Alcazar ◽

Anja Kopp ◽

...

Keyword(s):

Cell Death ◽

Inflammatory Responses ◽

Molecular Model ◽

Adaptor Protein ◽

Continuous Transition ◽

Danger Signals ◽

Caspase 1 ◽

Pyrin Domain ◽

Protein Elongation ◽

Family Cytokine

Inflammasomes sense intrinsic and extrinsic danger signals to trigger inflammatory responses and pyroptotic cell death. Homotypic pyrin domain (PYD) interactions of inflammasome forming Nod-like receptors with the adaptor protein ASC mediate oligomerization into helical filamentous assemblies. These supramolecular organizing centers recruit and activate caspase-1, which results in IL-1β family cytokine maturation and pyroptotic cell death. The molecular details of the critical step in signal transduction of inflammasome signaling, however, remain ill-defined. Here, we describe the cryo-EM structure of the human NLRP3 PYD filament at 3.6 Ang resolution. We identify a unique pattern of highly polar interface residues that form the homomeric interactions leading to characteristic filament ends that we designate as A- and B-end, respectively. Coupling a titration polymerization assay to cryo-EM, we demonstrate that the ASC adaptor protein elongation on NLRP3 PYD filament seeds is unidirectional, associating exclusively to the B-end of the NLRP3 filament. Notably, NLRP3 and ASC PYD filaments exhibit the same symmetry in rotation and axial rise per subunit, allowing for a continuous transition between NLRP3 as the nucleation seed and ASC as the elongator. Integrating the directionality of filament growth, we present a molecular model of the ASC speck consisting of active NLRP3-NEK7, ASC, and Caspase-1 proteins.

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