Bi-allelic KICS2 mutations impair KICSTOR complex-mediated mTORC1 regulation, causing intellectual disability and epilepsy.

Nutrient-dependent mTORC1 regulation upon amino acid deprivation is mediated by the KICSTOR complex, comprising SZT2, KPTN, ITFG2, and KICS2, recruiting GATOR1 to lysosomes. Previously, pathogenic SZT2 and KPTN variants have been associated with autosomal recessive intellectual disability and epileptic encephalopathy. We identified bi-allelic KICS2 variants in eleven affected individuals presenting with intellectual disability and epilepsy.

ERK activation waves coordinate mechanical cell competition leading to collective elimination via extrusion of bacterially infected cells.

Epithelial cells respond to infection with the intracellular bacterial pathogen Listeria monocytogenes by altering their mechanics to promote collective infected cell extrusion (CICE) and limit infection spread across cell monolayers. However, the underlying biochemical pathways remain elusive. Here, using in vitro (epithelial monolayers) and in vivo (zebrafish larvae) models of infection with L.

Implications of specific lysine residues within ataxin-3 for the molecular pathogenesis of Machado-Joseph disease.

Lysine residues are one of the main sites for posttranslational modifications of proteins, and lysine ubiquitination of the Machado-Joseph disease protein ataxin-3 is implicated in its cellular function and polyglutamine expansion-dependent toxicity. Despite previously undertaken efforts, the individual roles of specific lysine residues of the ataxin-3 sequence are not entirely understood and demand further analysis. By retaining single lysine residues of otherwise lysine-free wild-type and polyglutamine-expanded ataxin-3, we assessed the effects of a site-limited modifiability on ataxin-3 protein levels, aggregation propensity, localization, and stability.

Proteins released into the plant apoplast by the obligate parasitic protist Albugo selectively repress phyllosphere-associated bacteria.

Biotic and abiotic interactions shape natural microbial communities. The mechanisms behind microbe-microbe interactions, particularly those protein based, are not well understood. We hypothesize that released proteins with antimicrobial activity are a powerful and highly specific toolset to shape and defend plant niches.

SPRTN-dependent DPC degradation precedes repair of damaged DNA: a proof of concept revealed by the STAR assay.

DNA-protein crosslinks (DPCs), formed by the covalent conjugation of proteins to DNA, are toxic lesions that interfere with DNA metabolic processing and transcription. The development of an accurate biochemical assay for DPC isolation is a priority for the mechanistic understanding of their repair. Here, we propose the STAR assay for the direct quantification of DPCs, sensitive to physiologically relevant treatment conditions.

Glutamine prevents acute kidney injury by modulating oxidative stress and apoptosis in tubular epithelial cells.

Acute kidney injury (AKI) represents a common complication in critically ill patients that is associated with increased morbidity and mortality. In a murine AKI model induced by ischemia/reperfusion injury (IRI), we show that glutamine significantly decreases kidney damage and improves kidney function. We demonstrate that glutamine causes transcriptomic and proteomic reprogramming in murine renal tubular epithelial cells (TECs), resulting in decreased epithelial apoptosis, decreased neutrophil recruitment, and improved mitochondrial functionality and respiration provoked by an ameliorated oxidative phosphorylation.

Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.

Purpose: Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses.

Methods: Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls.

Pulmonary Surfactant Proteins Are Inhibited by Immunoglobulin A Autoantibodies in Severe COVID-19.

Coronavirus disease 2019 (COVID-19) can lead to acute respiratory distress syndrome with fatal outcomes. Evidence suggests that dysregulated immune responses, including autoimmunity, are key pathogenic factors. To assess whether IgA autoantibodies target lung-specific proteins and contribute to disease severity.

Profiling of time-dependent human plasma protein adsorption on non-coated and heparin-coated oxygenator membranes.

Patients with severe lung diseases are highly dependent on lung support systems. Despite many improvements, long-term use is not possible, mainly because of the strong body defence reactions (e.g.

Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder.

BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3.

Comparative Transcriptional Profiling of Motor Neuron Disorder-Associated Genes in Various Human Cell Culture Models.

Disease modeling requires appropriate cellular models that best mimic the underlying pathophysiology. Human origin and an adequate expression of the disease protein are pre-requisites that support information from a model to be meaningful. In this study we investigated expression profiles of (i) PBMCs and (ii) fibroblasts as patient derived cells as well as (iii) lymphoblasts and (iv) induced pluripotent stem cells (iPSC) as immortalized sources, and (v) iPSC-derived cortical neurons to assess their aptitude to model motor neuron diseases (MNDs) including hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA).

Efficient reduction of synthetic mRNA induced immune activation by simultaneous delivery of B18R encoding mRNA.

The application of synthetic modified messenger RNA (mRNA) is a promising approach for the treatment of a variety of diseases and vaccination. In the past few years, different modifications of synthetic mRNA were applied to render the mRNA more stable and less immunogenic. However, the repeated application of synthetic mRNA still requires the suppression of immune activation to avoid cell death and to allow a sufficient production of exogenous proteins.

Multi-omics discovery of exome-derived neoantigens in hepatocellular carcinoma.

Background: Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in HCCs.

Methods: In-depth multi-omics analyses included whole exome and transcriptome sequencing to define individual patient-specific search spaces of neoepitope candidates.

Staphylococcal Enterotoxins Dose-Dependently Modulate the Generation of Myeloid-Derived Suppressor Cells.

is one of the major human bacterial pathogens causing a broad spectrum of serious infections. Myeloid-derived suppressor cells (MDSC) represent an innate immune cell subset capable of regulating host-pathogen interactions, yet their role in the pathogenesis of infections remains incompletely defined. The aim of this study was to determine the influence of different strains and associated virulence factors on human MDSC generation.

Regulation of the opposing (p)ppGpp synthetase and hydrolase activities in a bifunctional RelA/SpoT homologue from Staphylococcus aureus.

The stringent response is characterized by (p)ppGpp synthesis resulting in repression of translation and reprogramming of the transcriptome. In Staphylococcus aureus, (p)ppGpp is synthesized by the long RSH (RelA/SpoT homolog) enzyme, RelSau or by one of the two short synthetases (RelP, RelQ). RSH enzymes are characterized by an N-terminal enzymatic domain bearing distinct motifs for (p)ppGpp synthetase or hydrolase activity and a C-terminal regulatory domain (CTD) containing conserved motifs (TGS, DC and ACT).

Identification and Functional Characterization of Phosphorylation Sites of the Human Papillomavirus 31 E8^E2 Protein.

The papillomavirus E2 protein regulates transcription, replication, and nuclear retention of viral genomes. Phosphorylation of E2 in the hinge region has been suggested to modulate protein stability, DNA-binding activity, and chromosomal attachment. The papillomavirus E8^E2 protein shares the hinge domain with E2 and acts as a repressor of viral replication.

Proteome and phosphoproteome analysis of commensally induced dendritic cell maturation states.

Dendritic cells (DCs) can shape the immune system towards an inflammatory or tolerant state depending on the bacterial antigens and the environment they encounter. In this study we provide a proteomic catalogue of differentially expressed proteins between distinct DC maturation states, brought about by bacteria that differ in their endotoxicity. To achieve this, we have performed proteomics and phosphoproteomics on murine DC cultures.

PHYSIOLOGY. Regulation of breathing by CO₂ requires the proton-activated receptor GPR4 in retrotrapezoid nucleus neurons.

Blood gas and tissue pH regulation depend on the ability of the brain to sense CO2 and/or H(+) and alter breathing appropriately, a homeostatic process called central respiratory chemosensitivity. We show that selective expression of the proton-activated receptor GPR4 in chemosensory neurons of the mouse retrotrapezoid nucleus (RTN) is required for CO2-stimulated breathing. Genetic deletion of GPR4 disrupted acidosis-dependent activation of RTN neurons, increased apnea frequency, and blunted ventilatory responses to CO2.

Janus kinase 3 regulates renal 25-hydroxyvitamin D 1α-hydroxylase expression, calcitriol formation, and phosphate metabolism.

Calcitriol, a powerful regulator of phosphate metabolism and immune response, is generated by 25-hydroxyvitamin D 1α-hydroxylase in the kidney and macrophages. Renal 1α-hydroxylase expression is suppressed by Klotho and FGF23, the expression of which is stimulated by calcitriol. Interferon γ (INFγ) regulates 1α-hydroxylase expression in macrophages through transcription factor interferon regulatory factor-1.

Quantitative proteomics of the human skin secretome reveal a reduction in immune defense mediators in ectodermal dysplasia patients.

In healthy human skin host defense molecules such as antimicrobial peptides (AMPs) contribute to skin immune homeostasis. In patients with the congenital disease ectodermal dysplasia (ED) skin integrity is disturbed and as a result patients have recurrent skin infections. The disease is characterized by developmental abnormalities of ectodermal derivatives and absent or reduced sweating.

The proton-activated receptor GPR4 modulates glucose homeostasis by increasing insulin sensitivity.

Background: The proton-activated G protein-coupled receptor GPR4 is expressed in many tissues including white adipose tissue. GPR4 is activated by extracellular protons in the physiological pH range (i.e.