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BioRxiv : the Preprint Server For... Sep 2023Hypoxic cancer cells resist many anti-neoplastic therapies and can seed recurrence. We found previously that PTP1B deficiency promotes HER2+ breast cancer cell death in...
Hypoxic cancer cells resist many anti-neoplastic therapies and can seed recurrence. We found previously that PTP1B deficiency promotes HER2+ breast cancer cell death in hypoxia by activating RNF213, an ∼600kDa protein containing AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) that also is implicated in Moyamoya disease (MMD), lipotoxicity, and innate immunity. Here we report that PTP1B and ABL1/2 reciprocally control RNF213 phosphorylation on tyrosine-1275. This phosphorylation promotes RNF213 oligomerization and RZ domain activation. The RZ domain ubiquitylates CYLD/SPATA2, and together with the LUBAC complex, induces their degradation. Decreased CYLD/SPATA2 causes NF-κB activation, which together with hypoxia-induced ER-stress triggers GDSMD-dependent pyroptosis. Mutagenesis experiments show that the RING domain negatively regulates the RZ domain. -deleted HER2+ cell-derived xenografts phenocopy the effects of PTP1B deficiency, and reconstituting knockout lines with RNF213 mutants shows that the RZ domain mediates PTP1B-dependent tumor cell death. Our results identify a novel, potentially targetable PTP1B/RNF213/CYCLD/SPATA pathway critical for controlling inflammatory cell death in hypoxic tumors that could be exploited to target hypoxic tumor cells, potentially turning "cold" tumors "hot". Our findings also reveal new insights into RNF213 regulation, and have potentially important implications for the pathogenesis of MMD, atherosclerosis, and inflammatory and auto-immune disorders.
PubMed: 37808759
DOI: 10.1101/2023.08.05.552118 -
Cold Spring Harbor Perspectives in... Jun 2024Decades of research have identified the pathological and pathophysiological hallmarks of Parkinson's disease (PD): profound deficit in brain dopamine and other...
Decades of research have identified the pathological and pathophysiological hallmarks of Parkinson's disease (PD): profound deficit in brain dopamine and other monoamines, pathological α-synuclein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, altered energy homeostasis, inflammation, and neuronal cell death. The purpose of this contribution is to present the phenocopy aspect, pathogenic, and etiologic nonhuman primate (NHP) models of PD to readers with limited prior knowledge of PD so that they are ready to start working on PD. How NHPs, the closest species to man on which we can model diseases, contribute to the knowledge progress and how these models represent an invaluable translational step in therapeutic development are highlighted.
PubMed: 38858083
DOI: 10.1101/cshperspect.a041612 -
Cell Reports Dec 2023Neurodegenerative disorders, such as Alzheimer's disease (AD) or Huntington's disease (HD), are linked to protein aggregate neurotoxicity. According to the "cholinergic...
Neurodegenerative disorders, such as Alzheimer's disease (AD) or Huntington's disease (HD), are linked to protein aggregate neurotoxicity. According to the "cholinergic hypothesis," loss of acetylcholine (ACh) signaling contributes to the AD pathology, and therapeutic restoration of ACh signaling is a common treatment strategy. How disease causation and the effect of ACh are linked to protein aggregation and neurotoxicity remains incompletely understood, thus limiting the development of more effective therapies. Here, we show that BAZ-2, the Caenorhabditis elegans ortholog of human BAZ2B, limits ACh signaling. baz-2 mutations reverse aggregation and toxicity of amyloid-beta as well as polyglutamine peptides, thereby restoring health and lifespan in nematode models of AD and HD, respectively. The neuroprotective effect of Δbaz-2 is mediated by choline acetyltransferase, phenocopied by ACh-esterase depletion, and dependent on ACh receptors. baz-2 reduction or ectopic ACh treatment augments proteostasis via induction of the endoplasmic reticulum unfolded protein response and the ubiquitin proteasome system.
Topics: Animals; Humans; Acetylcholine; Alzheimer Disease; Amyloid beta-Peptides; Bromodomain Containing Proteins; Caenorhabditis elegans; Huntington Disease; Proteostasis; Transcription Factors, General
PubMed: 38100354
DOI: 10.1016/j.celrep.2023.113577 -
Life Science Alliance Sep 2023Phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 5-phosphate (PI5P) are low-abundance phosphoinositides crucial for key cellular events such as endosomal...
Phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 5-phosphate (PI5P) are low-abundance phosphoinositides crucial for key cellular events such as endosomal trafficking and autophagy. Phosphatidylinositol 5-phosphate 4-kinase (PIP4K) is an enzyme that regulates PI5P in vivo but can act on both PI5P and PI3P in vitro. In this study, we report a role for PIP4K in regulating PI3P levels in Loss-of-function mutants of the only PIP4K gene show reduced cell size in salivary glands. PI3P levels are elevated in and reverting PI3P levels back towards WT, without changes in PI5P levels, can rescue the reduced cell size. mutants also show up-regulation in autophagy and the reduced cell size can be reverted by depleting Atg8a that is required for autophagy. Lastly, increasing PI3P levels in WT can phenocopy the reduction in cell size and associated autophagy up-regulation seen in Thus, our study reports a role for a PIP4K-regulated PI3P pool in the control of autophagy and cell size.
Topics: Animals; Autophagy; Cell Size; Drosophila; Endosomes
PubMed: 37316298
DOI: 10.26508/lsa.202301920 -
Current Opinion in Cardiology Sep 2023The aim of this study was to review imaging of myocardial hypertrophy in hypertrophic cardiomyopathy (HCM) and its phenocopies. The introduction of cardiac myosin... (Review)
Review
PURPOSE OF REVIEW
The aim of this study was to review imaging of myocardial hypertrophy in hypertrophic cardiomyopathy (HCM) and its phenocopies. The introduction of cardiac myosin inhibitors in HCM has emphasized the need for careful evaluation of the underlying cause of myocardial hypertrophy.
RECENT FINDINGS
Advances in imaging of myocardial hypertrophy have focused on improving precision, diagnosis, and predicting prognosis. From improved assessment of myocardial mass and function, to assessing myocardial fibrosis without the use of gadolinium, imaging continues to be the primary tool in understanding myocardial hypertrophy and its downstream effects. Advances in differentiating athlete's heart from HCM are noted, and the increasing rate of diagnosis in cardiac amyloidosis using noninvasive approaches is especially highlighted due to the implications on treatment approach. Finally, recent data on Fabry disease are shared as well as differentiating other phenocopies from HCM.
SUMMARY
Imaging hypertrophy in HCM and ruling out other phenocopies is central to the care of patients with HCM. This space will continue to rapidly evolve, as disease-modifying therapies are under investigation and being advanced to the clinic.
Topics: Humans; Diagnosis, Differential; Cardiomyopathy, Hypertrophic; Cardiomegaly; Magnetic Resonance Imaging, Cine; Contrast Media; Fibrosis
PubMed: 37421401
DOI: 10.1097/HCO.0000000000001070 -
Protein Science : a Publication of the... Sep 2023BAZ2A promotes migration and invasion in prostate cancer. Two chemical probes, the specific BAZ2-ICR, and the BAZ2/BRD9 cross-reactive GSK2801, interfere with the...
BAZ2A promotes migration and invasion in prostate cancer. Two chemical probes, the specific BAZ2-ICR, and the BAZ2/BRD9 cross-reactive GSK2801, interfere with the recognition of acetylated lysines in histones by the bromodomains of BAZ2A and of its BAZ2B paralog. The two chemical probes were tested in prostate cancer cell lines with opposite androgen susceptibility. BAZ2-ICR and GSK2801 showed different cellular efficacies in accordance with their unequal selectivity profiles. Concurrent inhibition of BAZ2 and BRD9 did not reproduce the effects observed with GSK2801, indicating possible off-targets for this chemical probe. On the other hand, the single BAZ2 inhibition by BAZ2-ICR did not phenocopy genetic ablation, demonstrating that bromodomain interference is not sufficient to strongly affect BAZ2A functionality and suggesting a PROTAC-based chemical ablation as an alternative optimization strategy and a possible therapeutic approach. In this context, we also present the crystallographic structures of BAZ2A in complex with the above chemical probes. Binding poses of TP-238 and GSK4027, chemical probes for the bromodomain subfamily I, and two ligands of the CBP/EP300 bromodomains identify additional headgroups for the development of BAZ2A ligands.
Topics: Male; Humans; Ligands; Chromosomal Proteins, Non-Histone; Indolizines; Prostatic Neoplasms; Transcription Factors; Transcription Factors, General
PubMed: 37574751
DOI: 10.1002/pro.4752 -
The American Journal of Cardiology Feb 2024Hypertrophic cardiomyopathy (HCM) is increasingly recognized and may benefit from the recent approval of new, targeted medical therapy. Successful management of HCM is... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is increasingly recognized and may benefit from the recent approval of new, targeted medical therapy. Successful management of HCM is dependent on early and accurate diagnosis. The lack of a definitive diagnostic test, the wide variation in phenotype and the commonness of phenocopy conditions, and the presence of normal or hyperdynamic left ventricular function in most patients makes HCM a condition that is highly dependent on imaging for all aspects of management including, diagnosis, classification, predicting risk of complications, detecting complications, identifying risk for ventricular arrhythmias, evaluating choice of therapy and monitoring therapy, intraprocedural guidance, and screening family members. Although echocardiographic imaging remains the mainstay in the diagnosis and subsequent management of HCM, this disease clearly requires multimethod imaging for various aspects of optimal patient care. Advances in echocardiography hardware and techniques, development and refinement of imaging with computed tomography, magnetic resonance, and nuclear scanning, and the emergence of very focused assessments such as diastology and fibrosis imaging have all advanced the diagnosis and management of HCM. In this review, we discuss the relative utility and evidence support for these imaging approaches to contribute to improve patient outcomes.
Topics: Humans; Cardiomyopathy, Hypertrophic; Magnetic Resonance Imaging; Echocardiography; Arrhythmias, Cardiac; Ventricular Function, Left
PubMed: 38368033
DOI: 10.1016/j.amjcard.2023.10.081 -
Research (Washington, D.C.) 2023Histone deacetylases (HDACs) are epigenetic regulators that play an important role in determining cell fate and maintaining cellular homeostasis. However, whether and...
Histone deacetylases (HDACs) are epigenetic regulators that play an important role in determining cell fate and maintaining cellular homeostasis. However, whether and how HDACs regulate iron metabolism and ferroptosis (an iron-dependent form of cell death) remain unclear. Here, the putative role of hepatic HDACs in regulating iron metabolism and ferroptosis was investigated using genetic mouse models. Mice lacking expression in the liver (-LKO mice) have significantly reduced hepatic mRNA (encoding the peptide hormone hepcidin) and altered iron homeostasis. Transcription profiling of -LKO mice suggests that the Hippo signaling pathway may be downstream of Hdac3. Moreover, using a Hippo pathway inhibitor and overexpressing the transcriptional regulator Yap (Yes-associated protein) significantly reduced mRNA levels. Using a promoter reporter assay, we then identified 2 Yap-binding repressor sites within the human promoter region. We also found that inhibiting Hdac3 led to increased translocation of Yap to the nucleus, suggesting activation of Yap. Notably, knock-in mice expressing a constitutively active form of Yap (Yap K342M) phenocopied the altered hepcidin levels observed in -LKO mice. Mechanistically, we show that iron-overload-induced ferroptosis underlies the liver injury that develops in -LKO mice, and knocking down Yap expression in -LKO mice reduces both iron-overload- and ferroptosis-induced liver injury. These results provide compelling evidence supporting the notion that HDAC3 regulates iron homeostasis via the Hippo/Yap pathway and may serve as a target for reducing ferroptosis in iron-overload-related diseases.
PubMed: 38034086
DOI: 10.34133/research.0281 -
Nature Communications Sep 2023HELLS/LSH (Helicase, Lymphoid Specific) is a SNF2-like chromatin remodelling protein involved in DNA methylation. Its loss-of-function in humans causes humoral...
HELLS/LSH (Helicase, Lymphoid Specific) is a SNF2-like chromatin remodelling protein involved in DNA methylation. Its loss-of-function in humans causes humoral immunodeficiency, called ICF4 syndrome (Immunodeficiency, Centromeric Instability, Facial anomalies). Here we show by our newly generated B-cell-specific Hells conditional knockout mouse model that HELLS plays a pivotal role in T-dependent B-cell responses. HELLS deficiency induces accelerated decay of germinal center (GC) B cells and impairs the generation of high affinity memory B cells and circulating antibodies. Mutant GC B cells undergo dramatic DNA hypomethylation and massive de-repression of evolutionary recent retrotransposons, which surprisingly does not directly affect their survival. Instead, they prematurely upregulate either memory B cell markers or the transcription factor ATF4, which is driving an mTORC1-dependent metabolic program typical of plasma cells. Treatment of wild type mice with a DNMT1-specific inhibitor phenocopies the accelerated kinetics, thus pointing towards DNA-methylation maintenance by HELLS being a crucial mechanism to fine-tune the GC transcriptional program and enable long-lasting humoral immunity.
Topics: Animals; Humans; Mice; B-Lymphocytes; DNA; DNA Helicases; DNA Methylation; Germinal Center; Plasma Cells
PubMed: 37709749
DOI: 10.1038/s41467-023-41317-3 -
The Journal of Clinical Investigation Dec 2023Foxp3-expressing Tregs employ multiple suppressive mechanisms to curtail conventional T cell (Tconv) responses and establish tissue homeostasis. How Foxp3 coordinates...
Foxp3-expressing Tregs employ multiple suppressive mechanisms to curtail conventional T cell (Tconv) responses and establish tissue homeostasis. How Foxp3 coordinates Treg contact-dependent suppressive function is not fully resolved. In this issue of the JCI, Wang and colleagues revealed that Foxp3-mediated inhibition of ryanodine receptor 2 (RyR2) led to strong Treg-DC interactions and enhanced immunosuppression. RyR2 depletion in Tconvs phenocopied this effect and equipped Tconvs with Treg-like suppressive function in multiple inflammatory or autoimmune contexts. This study provides molecular and therapeutic insights underlying how cell-cell contact limits immune reactivity.
Topics: Mice; Animals; T-Lymphocytes, Regulatory; Ryanodine Receptor Calcium Release Channel; Mice, Inbred C57BL; Immunosuppression Therapy; Forkhead Transcription Factors
PubMed: 38099491
DOI: 10.1172/JCI172986