Small GTPase ARL4C Associated with Various Cancers Affects Microtubule Nucleation.

The changes in the level of small GTPase ARL4C are associated with the initiation and progression of many different cancers. The content of ARL4C varies greatly between different tissues, and the induction of ARL4C expression leads to changes in cell morphology and proliferation. Although ARL4C can bind alpha-tubulin and affect intracellular transport, the role of ARL4C in the functioning of the tubulin cytoskeleton remained unclear.

T-cadherin modulates adipogenic differentiation in mesenchymal stem cells: insights into ligand interactions.

Introduction: T-cadherin, a non-canonical member of the cadherin superfamily, was initially identified for its involvement in homophilic recognition within the nervous and vascular systems. Apart from its adhesive function, T-cadherin acts as a receptor for two ligands: LDL, contributing to atherogenic processes, and HMW adiponectin, a hormone with well-known cardiovascular protective properties. However, the precise role of T-cadherin in adipose tissue remains elusive.

TLR priming licenses NAIP inflammasome activation by immunoevasive ligands.

NLR family, apoptosis inhibitory proteins (NAIPs) detect bacterial flagellin and structurally related components of bacterial type III secretion systems (T3SS), and recruit NLR family CARD domain containing protein 4 (NLRC4) and caspase-1 into an inflammasome complex that induces pyroptosis. NAIP/NLRC4 inflammasome assembly is initiated by the binding of a single NAIP to its cognate ligand, but a subset of bacterial flagellins or T3SS structural proteins are thought to evade NAIP/NLRC4 inflammasome sensing by not binding to their cognate NAIPs. Unlike other inflammasome components such as NLRP3, AIM2, or some NAIPs, NLRC4 is constitutively present in resting macrophages and not known to be induced by inflammatory signals.

Blockade of IKK signaling induces RIPK1-independent apoptosis in human macrophages.

Regulated cell death in response to microbial infection plays an important role in immune defense and is triggered by pathogen disruption of essential cellular pathways. Gram-negative bacterial pathogens in the Yersinia genus disrupt NF-κB signaling via translocated effectors injected by a type III secretion system, thereby preventing induction of cytokine production and antimicrobial defense. In murine models of infection, Yersinia blockade of NF-κB signaling triggers cell-extrinsic apoptosis through Receptor Interacting Serine-Threonine Protein Kinase 1 (RIPK1) and caspase-8, which is required for bacterial clearance and host survival.

Distinct sequential death complexes regulate pyroptosis and IL-1β release in response to blockade of immune signaling.

Pathogen infection of host cells triggers an inflammatory cell death termed pyroptosis via activation of inflammatory caspases. However, blockade of immune signaling kinases by the virulence factor YopJ triggers cell death involving both apoptotic caspase-8 and pyroptotic caspase-1. While caspase-1 is normally activated within inflammasomes, -induced caspase-1 activation is independent of known inflammasome components.

impacts epithelial turnover and is resistant to induced death of the host cell.

Unlabelled: Infection with the apicomplexan parasite is a leading cause of diarrheal disease. Cryptosporidiosis is of particular importance in infants and shows a strong association with malnutrition, both as a risk factor and as a consequence. invades and replicates within the small intestine epithelial cells.

Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects.

Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in the COVID-19 vaccines and late-stage clinical studies in other indications. However, we and others have shown that LNPs induce severe inflammation, and massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids and analyses of signaling pathways, we elucidate the mechanisms of LNP-associated inflammation and demonstrate solutions.

A TNF-IL-1 circuit controls Yersinia within intestinal pyogranulomas.

Tumor necrosis factor (TNF) is a pleiotropic inflammatory cytokine that mediates antimicrobial defense and granuloma formation in response to infection by numerous pathogens. We previously reported that Yersinia pseudotuberculosis colonizes the intestinal mucosa and induces the recruitment of neutrophils and inflammatory monocytes into organized immune structures termed pyogranulomas (PG) that control Yersinia infection. Inflammatory monocytes are essential for the control and clearance of Yersinia within intestinal PG, but how monocytes mediate Yersinia restriction is poorly understood.

T-Cadherin Deficiency Is Associated with Increased Blood Pressure after Physical Activity.

T-cadherin is a regulator of blood vessel remodeling and angiogenesis, involved in adiponectin-mediated protective effects in the cardiovascular system and in skeletal muscles. GWAS study has previously demonstrated a SNP in the gene to be associated with hypertension. However, the role of T-cadherin in regulating blood pressure has not been experimentally elucidated.

Sequentially activated death complexes regulate pyroptosis and IL-1β release in response to blockade of immune signaling.

The virulence factor YopJ potently inhibits immune signaling in macrophages by blocking activation of the signaling kinases TAK1 and IKK. In response, macrophages trigger a backup pathway of host defense that mediates cell death via the apoptotic enzyme caspase-8 and pyroptotic enzyme caspase-1. While caspase-1 is normally activated within multiprotein inflammasome complexes that contain the adaptor ASC and NLRs, which act as sensors of pathogen virulence, caspase-1 activation following blockade of TAK1/IKK surprisingly requires caspase-8 and is independent of all known inflammasome components.

Collab or Cancel? Bacterial Influencers of Inflammasome Signaling.

The immune system of multicellular organisms protects them from harmful microbes. To establish an infection in the face of host immune responses, pathogens must evolve specific strategies to target immune defense mechanisms. One such defense is the formation of intracellular protein complexes, termed inflammasomes, that are triggered by the detection of microbial components and the disruption of homeostatic processes that occur during bacterial infection.

deploys type III-secreted effectors to evade caspase-4 inflammasome activation in human cells.

are responsible for significant disease burden in humans, ranging from recurrent disease outbreaks (yersiniosis) to pandemics ( plague). Together with rising antibiotic resistance rates, there is a critical need to better understand pathogenesis and host immune mechanisms, as this information will aid in developing improved immunomodulatory therapeutics. Inflammasome responses in human cells are less studied relative to murine models of infection, though recent studies have uncovered key differences in inflammasome responses between mice and humans.

Immunology: NACHT domain proteins get a prokaryotic origin story.

The NACHT domain is found in eukaryotic pattern recognition receptors that promote anti-microbial defense, mediating their oligomerization into immune signaling complexes. Kibby et al. uncover a superfamily of prokaryotic NACHT-containing proteins and demonstrate that some members of this family mediate anti-phage defense.

Inflammasomes primarily restrict cytosolic replication within human macrophages.

serovar Typhimurium is a facultative intracellular pathogen that utilizes its type III secretion systems (T3SSs) to inject virulence factors into host cells and colonize the host. In turn, a subset of cytosolic immune receptors respond to T3SS ligands by forming multimeric signaling complexes called inflammasomes, which activate caspases that induce interleukin-1 (IL-1) family cytokine release and an inflammatory form of cell death called pyroptosis. Human macrophages mount a multifaceted inflammasome response to infection that ultimately restricts intracellular bacterial replication.

Effect of vitamin D on regression to normal glucose regulation and individual glycemic measures: A secondary analysis among participants adherent to the trial protocol in the randomized clinical trial vitamin D and type 2 diabetes (D2d) study.

Aims: To examine the effect of vitamin D on regression to normal glucose regulation (NGR) and individual glycemic measures in the D2d study.

Methods: In per-protocol analyses, we examined time to new-onset diabetes; time to new-onset NGR defined as first occurrence of: 2-or-3 glycemic criteria in the normal range (NGR-1) or fasting plasma glucose (FPG) and 2-hour post-load-glucose (2hPG) in the normal range (NGR-2); proportion meeting NGR at the last study visit; and change in FPG, 2hPG, and HbA1c.

Results: Among 2423 participants, hazard ratio [HR] for diabetes was 0.

TNF licenses macrophages to undergo rapid caspase-1, -11, and -8-mediated cell death that restricts Legionella pneumophila infection.

The inflammatory cytokine tumor necrosis factor (TNF) is necessary for host defense against many intracellular pathogens, including Legionella pneumophila. Legionella causes the severe pneumonia Legionnaires' disease and predominantly affects individuals with a suppressed immune system, including those receiving therapeutic TNF blockade to treat autoinflammatory disorders. TNF induces pro-inflammatory gene expression, cellular proliferation, and survival signals in certain contexts, but can also trigger programmed cell death in others.

TLR priming licenses NAIP inflammasome activation by immunoevasive ligands.

NLR family, apoptosis inhibitory proteins (NAIPs) detect bacterial flagellin and structurally related components of bacterial type III secretion systems (T3SS), and recruit NLR family, CARD domain containing protein 4 (NLRC4) and caspase-1 into an inflammasome complex that induces pyroptosis. NAIP/NLRC4 inflammasome assembly is initiated by the binding of a single NAIP to its cognate ligand, but a subset of bacterial flagellins or T3SS structural proteins are thought to evade NAIP/NLRC4 inflammasome sensing by not binding to their cognate NAIPs. Unlike other inflammasome components such as NLRP3, AIM2, or some NAIPs, NLRC4 is constitutively present in resting macrophages, and not thought to be regulated by inflammatory signals.

A TNF-IL-1 circuit controls within intestinal granulomas.

Tumor necrosis factor (TNF) is a pleiotropic inflammatory cytokine that mediates antimicrobial defense and granuloma formation in response to infection by numerous pathogens. colonizes the intestinal mucosa and induces recruitment of neutrophils and inflammatory monocytes into organized immune structures termed pyogranulomas that control the bacterial infection. Inflammatory monocytes are essential for control and clearance of within intestinal pyogranulomas, but how monocytes mediate restriction is poorly understood.

Arresting microbiome development limits immune system maturation and resistance to infection in mice.

Disruptions to the intestinal microbiome during weaning lead to negative effects on host immune function. However, the critical host-microbe interactions during weaning that are required for immune system development remain poorly understood. We find that restricting microbiome maturation during weaning stunts immune system development and increases susceptibility to enteric infection.

Inflammatory monocytes promote granuloma control of Yersinia infection.

Granulomas are organized immune cell aggregates formed in response to chronic infection or antigen persistence. The bacterial pathogen Yersinia pseudotuberculosis (Yp) blocks innate inflammatory signalling and immune defence, inducing neutrophil-rich pyogranulomas (PGs) within lymphoid tissues. Here we uncover that Yp also triggers PG formation within the murine intestinal mucosa.

Type III-Secreted Effectors Evade the Caspase-4 Inflammasome in Human Cells.

are gram-negative zoonotic bacteria that use a type III secretion system (T3SS) to inject outer proteins (Yops) into the host cytosol to subvert essential components of innate immune signaling. However, virulence activities can elicit activation of inflammasomes, which lead to inflammatory cell death and cytokine release to contain infection. activation and evasion of inflammasomes have been characterized in murine macrophages but remain poorly defined in human cells, particularly intestinal epithelial cells (IECs), a primary site of intestinal infection.

Yersinia interactions with regulated cell death pathways.

Cell death in response to infection is conserved across all kingdoms of life. In metazoans, cell death upon bacterial infection is primarily carried out by the cysteine and aspartate protease and receptor-interacting serine/threonine protein kinase families. The Gram-negative bacterial genus Yersinia includes pathogens that cause disease in humans and other animals ranging from plague to gastrointestinal infections.

Divergent Contribution of the Golgi Apparatus to Microtubule Organization in Related Cell Lines.

Membrane trafficking in interphase animal cells is accomplished mostly along the microtubules. Microtubules are often organized radially by the microtubule-organizing center to coordinate intracellular transport. Along with the centrosome, the Golgi often serves as a microtubule-organizing center, capable of nucleating and retaining microtubules.