Signalling by co-operative higher-order assembly formation: linking evidence at molecular and cellular levels.

The concept of higher-order assembly signalling or signalling by co-operative assembly formation (SCAF) was proposed based on the structures of signalling assemblies formed by proteins featuring domains from the death-fold family and the Toll/interleukin-1 receptor domain family. Because these domains form filamentous assemblies upon stimulation and activate downstream pathways through induced proximity, they were envisioned to sharpen response thresholds through the extreme co-operativity of higher-order assembly. Recent findings demonstrate that a central feature of the SCAF mechanism is the nucleation barrier that allows a switch-like, digital or 'all-or-none' response to minute stimuli.

Chemical inhibition of a bacterial immune system 1.

The rise of antibiotic resistance motivates a revived interest in phage therapy. However, bacteria possess dozens of anti-bacteriophage immune systems that confer resistance to therapeutic phages. Chemical inhibitors of these anti-phage immune systems could be employed as adjuvants to overcome resistance in phage-based therapies.

Structural basis for TIR domain-mediated innate immune signaling by Toll-like receptor adaptors TRIF and TRAM.

Innate immunity relies on Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns. The TIR (Toll/interleukin-1 receptor) domain-containing TLR adaptors TRIF (TIR domain-containing adaptor-inducing interferon-β) and TRAM (TRIF-related adaptor molecule) are essential for MyD88-independent TLR signaling. However, the structural basis of TRIF and TRAM TIR domain-based signaling remains unclear.

Structural characterization of macro domain-containing Thoeris antiphage defense systems.

Thoeris defense systems protect bacteria from infection by phages via abortive infection. In these systems, ThsB proteins serve as sensors of infection and generate signaling nucleotides that activate ThsA effectors. Silent information regulator and SMF/DprA-LOG (SIR2-SLOG) containing ThsA effectors are activated by cyclic ADP-ribose (ADPR) isomers 2'cADPR and 3'cADPR, triggering abortive infection via nicotinamide adenine dinucleotide (NAD) depletion.

Tetramerization is essential for the enzymatic function of the virulence factor UDP-glucose pyrophosphorylase.

Multidrug-resistant bacteria such as the opportunistic pathogen , which causes life-threatening infections especially in immunocompromised individuals and cystic fibrosis patients, pose an increasing threat to public health. In the search for new treatment options, uridine diphosphate-glucose pyrophosphorylase (PaUGP) has been proposed as a novel drug target because it is required for the biosynthesis of important virulence factors and linked to pathogenicity in animal models. Here, we show that UGP-deficient exhibits severely reduced virulence against human lung tissue and cells, emphasizing the enzyme's suitability as a drug target.

Core hyphosphere microbiota of Fusarium oxysporum f. sp. niveum.

Background: Bacteria and fungi are dynamically interconnected, leading to beneficial or antagonistic relationships with plants. Within this interkingdom interaction, the microbial community directly associated with the pathogen make up the pathobiome. While the overall soil bacterial community associated with Fusarium wilt diseases has been widely examined, the specific bacterial populations that directly interact with the Fusarium wilt pathogens are yet to be discovered.

Metabolite Signature of Life's Essential 8 and Risk of Coronary Heart Disease Among Low-Income Black and White Americans.

Background: Life's essential 8 (LE8) is a comprehensive construct of cardiovascular health. Yet, little is known about the LE8 score, its metabolic correlates, and their predictive implications among Black Americans and low-income individuals.

Methods: In a nested case-control study of coronary heart disease (CHD) among 299 pairs of Black and 298 pairs of White low-income Americans from the Southern Community Cohort Study, we estimated LE8 score and applied untargeted plasma metabolomics and elastic net with leave-one-out cross-validation to identify metabolite signature (MetaSig) of LE8.

Community-Based Interventions to Address Disparities in Cardiometabolic Diseases Among Minoritized Racial and Ethnic Groups.

Purpose Of Review: Cardiometabolic diseases (CMDs) are leading causes of death and disproportionally impact historically marginalized racial/ethnic groups in the United States. The American Heart Association developed the Life's Essential 8 (LE8) to promote optimal cardiovascular health (CVH) through eight health behaviors and health factors. The purpose of this review is to summarize contemporary community-engaged research (CER) studies incorporating the LE8 framework among racial/ethnic groups.

Metabolite Signature of Life's Essential 8 and Risk of Coronary Heart Disease among Low-Income Black and White Americans.

Background And Aims: Life's Essential 8 (LE8) is a comprehensive construct of cardiovascular health. Yet, little is known about LE8 score, its metabolic correlates, and their predictive implications among Black Americans and low-income individuals.

Methods: In a nested case-control study of coronary heart disease (CHD) among 598 Black and 596 White low-income Americans, we estimated LE8 score, conducted untargeted plasma metabolites profiling, and used elastic net with leave-one-out cross-validation to identify metabolite signature (MetaSig) of LE8.

TIR domain-associated nucleotides with functions in plant immunity and beyond.

TIR (Toll/interlukin-1 receptor) domains are found in archaea, bacteria and eukaryotes, featured in proteins generally associated with immune functions. In plants, they are found in a large group of NLRs (nucleotide-binding leucine-rich repeat receptors), NLR-like proteins and TIR-only proteins. They are also present in effector proteins from phytopathogenic bacteria that are associated with suppression of host immunity.

Toll/interleukin-1 receptor domains in bacterial and plant immunity.

The Toll/interleukin-1 receptor (TIR) domain is found in animal, plant, and bacterial immune systems. It was first described as a protein-protein interaction module mediating signalling downstream of the Toll-like receptor and interleukin-1 receptor families in animals. However, studies of the pro-neurodegenerative protein sterile alpha and TIR motif containing 1, plant immune receptors, and many bacterial TIR domain-containing proteins revealed that TIR domains have enzymatic activities and can produce diverse nucleotide products using nicotinamide adenine dinucleotide (NAD) or nucleic acids as substrates.

SARM1-Dependent Axon Degeneration: Nucleotide Signaling, Neurodegenerative Disorders, Toxicity, and Therapeutic Opportunities.

Axons are an essential component of the nervous system, and axon degeneration is an early feature of many neurodegenerative disorders. The NAD metabolome plays an essential role in regulating axonal integrity. Axonal levels of NAD and its precursor NMN are controlled in large part by the NAD synthesizing survival factor NMNAT2 and the pro-neurodegenerative NADase SARM1, whose activation triggers axon destruction.

Plant and prokaryotic TIR domains generate distinct cyclic ADPR NADase products.

Toll/interleukin-1 receptor (TIR) domain proteins function in cell death and immunity. In plants and bacteria, TIR domains are often enzymes that produce isomers of cyclic adenosine 5'-diphosphate-ribose (cADPR) as putative immune signaling molecules. The identity and functional conservation of cADPR isomer signals is unclear.

Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling.

Cyclic adenosine diphosphate (ADP)-ribose (cADPR) isomers are signaling molecules produced by bacterial and plant Toll/interleukin-1 receptor (TIR) domains via nicotinamide adenine dinucleotide (oxidized form) (NAD) hydrolysis. We show that v-cADPR (2'cADPR) and v2-cADPR (3'cADPR) isomers are cyclized by O-glycosidic bond formation between the ribose moieties in ADPR. Structures of 2'cADPR-producing TIR domains reveal conformational changes that lead to an active assembly that resembles those of Toll-like receptor adaptor TIR domains.

Ucl fimbriae regulation and glycan receptor specificity contribute to gut colonisation by extra-intestinal pathogenic Escherichia coli.

Extra-intestinal pathogenic Escherichia coli (ExPEC) belong to a critical priority group of antibiotic resistant pathogens. ExPEC establish gut reservoirs that seed infection of the urinary tract and bloodstream, but the mechanisms of gut colonisation remain to be properly understood. Ucl fimbriae are attachment organelles that facilitate ExPEC adherence.

Structural basis of SARM1 activation, substrate recognition, and inhibition by small molecules.

The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration and a therapeutic target for several neurodegenerative conditions. We show that a potent SARM1 inhibitor undergoes base exchange with the nicotinamide moiety of nicotinamide adenine dinucleotide (NAD) to produce the bona fide inhibitor 1AD. We report structures of SARM1 in complex with 1AD, NAD mimetics and the allosteric activator nicotinamide mononucleotide (NMN).

Structural and biochemical characterization of Acinetobacter baumannii ZnuA.

Acinetobacter baumannii is a Gram-negative nosocomial pathogen associated with significant disease. Crucial to the survival and pathogenesis of A. baumannii is the ability to acquire essential micronutrients such as Zn(II).

Discovery of Cofactor Competitive Inhibitors against the Human Methyltransferase Fibrillarin.

Fibrillarin (FBL) is an essential and evolutionarily highly conserved S-adenosyl methionine (SAM) dependent methyltransferase. It is the catalytic component of a multiprotein complex that facilitates 2'--methylation of ribosomal RNAs (rRNAs), a modification essential for accurate and efficient protein synthesis in eukaryotic cells. It was recently established that human FBL (hFBL) is critical for Nipah, Hendra, and respiratory syncytial virus infections.

Crystal structure of the Toll/interleukin-1 receptor (TIR) domain of IL-1R10 provides structural insights into TIR domain signalling.

The Toll/interleukin-1 receptor (TIR) domains are key innate immune signalling modules. Here, we present the crystal structure of the TIR domain of human interleukin-1 receptor 10 (IL-1R10), also called interleukin 1 receptor accessory protein like 2. It is similar to that of IL-1R9 (IL-1RAPL1) but shows significant structural differences to those from Toll-like receptors (TLRs) and the adaptor proteins MyD88 adaptor-like protein (MAL) and MyD88.

Neurotoxin-mediated potent activation of the axon degeneration regulator SARM1.

Axon loss underlies symptom onset and progression in many neurodegenerative disorders. Axon degeneration in injury and disease is promoted by activation of the NAD-consuming enzyme SARM1. Here, we report a novel activator of SARM1, a metabolite of the pesticide and neurotoxin vacor.