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TMBIM6/BI-1 is an intracellular environmental regulator that induces paraptosis in cancer via ROS and Calcium-activated ERAD II pathways
Transmembrane B cell lymphoma 2-associated X protein inhibitor motif-containing (TMBIM) 6, also known as Bax Inhibitor-1 (BI-1), has been heavily researched for its cytoprotective functions. TMBIM6 functional diversity includes modulating cell survival, stress, metabolism, cytoskeletal dynamics, organelle function, regulating cytosolic acidification, calcium, and reactive oxygen species (ROS). Clinical research shows TMBIM6 plays a key role in many of the world’s top diseases/injuries (i.e., Alzheimer’s, Parkinson’s, diabetes, obesity, brain injury, liver disease, heart disease, aging, etc.), including cancer, where TMBIM6 expression impacts patient survival, chemoresistance, cancer progression, and metastasis. We show TMBIM6 is activated by, and undergoes, different conformational changes that dictate its function following a significant change in the cell’s IntraCellular Environment (ICE). TMBIM6 agonism, following ICE change, can help the cell overcome multiple stresses including toxin exposure, viral infection, wound healing, and excitotoxicity. However, in cancer cells TMBIM6 agonism results in rapid paraptotic induction irrespective of the cancer type, sub-type, genotype or phenotype. Furthermore, the level of TMBIM6 expression in cancer did not dictate the level of paraptotic induction; however, it did dictate the rate at which paraptosis occurred. TMBIM6 agonism did not induce paraptosis in cancer via canonical routes involving p38 MAPK, JNK, ERK, UPR, autophagy, proteasomes, or Caspase-9. Instead, TMBIM6 agonism in cancer upregulates cytosolic Ca2+ and ROS, activates lysosome biogenesis, and induces paraptosis via ERAD II mechanisms. In xenograft models, we show TMBIM6 agonism induces rapid cancer cell death with no toxicity, even at high doses of TMBIM6 agonist (>450 mg/kg). In summary, this study shows TMBIM6’s functional diversity is only activated by severe ICE change in diseased/injured cells, highlighting its transformative potential as a therapeutic target across various diseases and injuries, including cancer.
Journal Article
Salmonella bongori Provides Insights into the Evolution of the Salmonellae
The genus Salmonella contains two species, S. bongori and S. enterica. Compared to the well-studied S. enterica there is a marked lack of information regarding the genetic makeup and diversity of S. bongori. S. bongori has been found predominantly associated with cold-blooded animals, but it can infect humans. To define the phylogeny of this species, and compare it to S. enterica, we have sequenced 28 isolates representing most of the known diversity of S. bongori. This cross-species analysis allowed us to confidently differentiate ancestral functions from those acquired following speciation, which include both metabolic and virulence-associated capacities. We show that, although S. bongori inherited a basic set of Salmonella common virulence functions, it has subsequently elaborated on this in a different direction to S. enterica. It is an established feature of S. enterica evolution that the acquisition of the type III secretion systems (T3SS-1 and T3SS-2) has been followed by the sequential acquisition of genes encoding secreted targets, termed effectors proteins. We show that this is also true of S. bongori, which has acquired an array of novel effector proteins (sboA-L). All but two of these effectors have no significant S. enterica homologues and instead are highly similar to those found in enteropathogenic Escherichia coli (EPEC). Remarkably, SboH is found to be a chimeric effector protein, encoded by a fusion of the T3SS-1 effector gene sopA and a gene highly similar to the EPEC effector nleH from enteropathogenic E. coli. We demonstrate that representatives of these new effectors are translocated and that SboH, similarly to NleH, blocks intrinsic apoptotic pathways while being targeted to the mitochondria by the SopA part of the fusion. This work suggests that S. bongori has inherited the ancestral Salmonella virulence gene set, but has adapted by incorporating virulence determinants that resemble those employed by EPEC.
Journal Article
Jake the fake keeps it real
Having faked his way into the Music and Art Academy, a performing arts school for gifted students where his talented older sister rules, sixth-grader Jake, a jokester who can barely play an instrument, will have to think of something quick before the last laugh is on him.
BOOK
Wildfire smoke and pediatric asthma control in the Northeastern United States: a cross-sectional study
Background
Poor air quality due to smoke from distant wildfires is a growing risk for the Northeastern United States, a region largely unaffected by these events until recently. Despite this emerging threat, few studies have examined the effect of wildfire smoke on respiratory health in this region. We investigated the association between wildfire smoke exposure and pediatric asthma control in Vermont and upstate New York.
Methods
We extracted data from the electronic health records of youth aged 3–21 years diagnosed with asthma within a single regional healthcare system and included three clinical measures of asthma control: Test for Respiratory and Asthma Control in Kids (3–4 years), Asthma Therapy Assessment Questionnaire (5–21 years), and the National Heart, Lung and Blood Institute (NHLBI) asthma control guidelines (3–21 years). We first compared asthma control in the smoke-affected summer of 2023 to the largely unaffected summers of 2022 and 2024 using regression models, controlling for pollen exposure. We then obtained airborne particulate matter (PM
2.5
) values within ZIP codes and used regression models to investigate the association between asthma control and PM
2.5
during the smoke-affected summer of 2023.
Results
The study sample included 1,217 encounters (mean age 9.1 ± 4.4 years, 57% male). Asthma control was significantly worse in the severely smoke-affected summer of 2023 versus 2022 for two of the three clinical measures but was not different between 2023 and 2024 for any of the clinical measures. Within summer 2023, there were no significant associations between ZIP code–level PM
2.5
and asthma control for any of the three clinical measures.
Conclusions
Wildfire smoke exposure in the Northeast was associated with decreased asthma control in this pediatric population, though not consistently across years and all clinical measures. As climate change drives longer and more intense wildfire seasons, continued monitoring is needed to understand the impact on pediatric respiratory health in this historically low-exposed region.
Journal Article
NleH effectors interact with Bax inhibitor-1 to block apoptosis during enteropathogenic Escherichia coli infection
The human pathogens enteropathogenic (EPEC) and enterohemorrhagic Escherichia coli and the related mouse pathogen Citrobacter rodentium subvert a variety of host cell signaling pathways via their plethora of type III secreted effectors, including triggering of an early apoptotic response. EPEC-infected cells do not develop late apoptotic symptoms, however. In this study we demonstrate that the NleH family effectors, homologs of the Shigella effector kinase OspG, blocks apoptosis. During EPEC infection, NleH effectors inhibit elevation of cytosolic Ca²⁺ concentrations, nuclear condensation, caspase-3 activation, and membrane blebbing and promote cell survival. NleH1 alone is sufficient to prevent procaspase-3 cleavage induced by the proapoptotic compounds staurosporine, brefeldin A, and tunicamycin. Using C. rodentium, we found that NleH inhibits procaspase-3 cleavage at the bacterial attachment sites in vivo. A yeast two-hybrid screen identified the endoplasmic reticulum six-transmembrane protein Bax inhibitor-1 (BI-1) as an NleH-interacting partner. We mapped the NleH-binding site to the N-terminal 40 amino acids of BI-1. Knockdown of BI-1 resulted in the loss of NleH's antiapoptotic activity. These results indicate that NleH effectors are inhibitors of apoptosis that may act through BI-1 to carry out their cytoprotective function.
Journal Article
A type III effector antagonizes death receptor signalling during bacterial gut infection
Colonizing enteric bacteria are shown to inhibit the antimicrobial process of host cell apoptosis through the action of NleB1, a type III secretion system effector with
N-
acetylglucosamine transferase activity, which can bind and modify eukaryotic death-domain-containing proteins.
Virulence mechanism of bacterial effector NleB
Previous studies identified a group of effectors from enteropathogenic
Escherichia coli
that can inhibit host nuclear factor-κB (NF-κB) signalling, yet only one of them, known as NleB, is required for bacterial virulence
in vivo
. Two papers published in this issue demonstrate the unique mechanism of action of NleB. It directly targets death receptor signalling complexes, binding to the death domains (DDs) of multiple DD-containing proteins including the TNF receptor, FAS, RIPK1, TRADD and FADD. NleB is shown to function as an
N
-acetylglucosamine (GlcNAc) transferase that modifies a conserved DD arginine, blocking the receptor-adapter interaction. These findings suggest that GlcNAc modification is essential for bacterial virulence and can regulate death receptor signalling.
Successful infection by enteric bacterial pathogens depends on the ability of the bacteria to colonize the gut, replicate in host tissues and disseminate to other hosts. Pathogens such as
Salmonella
,
Shigella
and enteropathogenic and enterohaemorrhagic (EPEC and EHEC, respectively)
Escherichia coli
use a type III secretion system (T3SS) to deliver virulence effector proteins into host cells during infection that promote colonization and interfere with antimicrobial host responses
1
,
2
,
3
. Here we report that the T3SS effector NleB1 from EPEC binds to host cell death-domain-containing proteins and thereby inhibits death receptor signalling. Protein interaction studies identified FADD, TRADD and RIPK1 as binding partners of NleB1. NleB1 expressed ectopically or injected by the bacterial T3SS prevented Fas ligand or TNF-induced formation of the canonical death-inducing signalling complex (DISC) and proteolytic activation of caspase-8, an essential step in death-receptor-induced apoptosis. This inhibition depended on the
N
-acetylglucosamine transferase activity of NleB1, which specifically modified Arg 117 in the death domain of FADD. The importance of the death receptor apoptotic pathway to host defence was demonstrated using mice deficient in the FAS signalling pathway, which showed delayed clearance of the EPEC-like mouse pathogen
Citrobacter rodentium
and reversion to virulence of an
nleB
mutant. The activity of NleB suggests that EPEC and other attaching and effacing pathogens antagonize death-receptor-induced apoptosis of infected cells, thereby blocking a major antimicrobial host response.
Journal Article
Associations of actigraphy measures of sleep duration and continuity with executive function, vigilance, and fine motor control in children with snoring and mild sleep-disordered breathing
Study Objectives:
Children with snoring and mild sleep-disordered breathing may be at increased risk for neurocognitive deficits despite few obstructive events. We hypothesized that actigraphy-based sleep duration and continuity associate with neurobehavioral functioning and explored whether these associations vary by demographic and socioeconomic factors.
Methods:
298 children enrolled in the Pediatric Adenotonsillectomy Trial, ages 3 to 12.9 years, 47.3% from racial or ethnic minority groups, with habitual snoring and an apnea-hypopnea index < 3 were studied with actigraphy (mean 7.5 ± 1.4 days) and completed a computerized vigilance task (Go-No-Go) and a test of fine motor control (9-Hole Pegboard). Caregivers completed the Behavior Rating Inventory of Executive Function. Regression analyses evaluated associations between sleep exposures (24-hour and nocturnal sleep duration, sleep fragmentation index, sleep efficiency) with the Behavior Rating Inventory of Executive Function Global Executive Composite index, pegboard completion time (fine motor control), and vigilance (d prime on the Go-No-Go), adjusting for demographic factors and study design measures.
Results:
Longer sleep duration, higher sleep efficiency, and lower sleep fragmentation were associated with better executive function; each additional hour of sleep over 24 hours associated with more than a 3-point improvement in executive function (
P
= .002). Longer nocturnal sleep (
P
= .02) and less sleep fragmentation (
P
= .001) were associated with better fine motor control. Stronger associations were observed for boys and children less than 6 years old.
Conclusions:
Sleep quantity and continuity are associated with neurocognitive functioning in children with mild sleep-disordered breathing, supporting efforts to target these sleep health parameters as part of interventions for reducing neurobehavioral morbidity.
Clinical Trial Registration:
Registry: ClinicalTrials.gov; Name: Pediatric Adenotonsillectomy for Snoring (PATS); URL:
https://clinicaltrials.gov/ct2/show/NCT02562040
; Identifier: NCT02562040.
Citation:
Robinson KA, Wei Z, Radcliffe J, et al. Associations of actigraphy measures of sleep duration and continuity with executive function, vigilance, and fine motor control in children with snoring and mild sleep-disordered breathing.
J Clin Sleep Med
. 2023;19(9):1595–1603.
Journal Article