Biology subjects

Bock, F.

Publications and source records attributed to Bock, F..

7 recordsLinked to original sources

bioRxiv2025

Alpha Parvin Promotes Glucose Uptake and Metabolism in Skeletal Muscle with Minimal Influence on Hepatic Insulin Sensitivity

Skeletal muscle and liver insulin resistance are early features in the sequelae of type 2 diabetes. Integrins are extracellular matrix receptors expressed on skeletal muscle cells and hepatocytes and have been implicated in modulating obesity-associated insulin resistance. Integrins regulate cell function through intracellular proteins including the ILK-PINCH-Parvin (IPP) complex. ILK promotes skeletal muscle and liver insulin resistance in diet-induced obesity in mice but the role of Parvin is unexplored. Here we demonstrate that hepatocyte specific deletion of -Parvin had only minimal influence on endogenous glucose production or whole-body insulin sensitivity. In contrast, deletion of -Parvin in skeletal muscle caused a striking reduction in muscle glucose uptake during an insulin clamp in lean mice which was not exacerbated by diet-induced obesity. Insulin-mediated GLUT4 membrane recruitment was impaired in mutant muscles which displayed significant morphological abnormalities due to actin cytoskeleton dysfunction. Consistent with severe muscular dysfunction, mitochondrial oxidative capacity and aerobic exercise capacity were blunted in muscle -Parvin-null mice. Thus, -Parvin has a minor role in liver insulin action but is required for insulin-stimulated glucose uptake in skeletal muscle due to its role in actin cytoskeleton regulation. These data suggest that individual IPP complex proteins link cell structure to metabolism via distinct mechanisms in a tissue-specific fashion.

physiology↗

bioRxiv2025

Disruption of Iron Metabolism Resulting from Dmt1/Slc11A2 Deficiency Compromises Notch Protein Degradation and Transcriptional Activation

Notch receptor activation requires {gamma}-secretase-mediated release of Notch intracellular domain 1(NICD1) to regulate gene transcription. Here, we identify the proton-driven Solute carrier 11A2 (Slc11A2) or divalent metal transport protein Dmt1 as an inhibitor of Notch signaling via regulating iron homeostasis and lysosomal integrity. Dmt1 loss reduces ferritin levels and increases labile Fe2+, causing elevated reactive oxygen species (ROS) and lipid peroxidation. These changes compromise lysosomal function and impair degradation of S3-Val1744 cleaved NICD1, resulting in its accumulation. Dmt1 has isoforms with or without an iron response element (IRE): Re-expressing Dmt1+IRE robustly increases ferritin heavy-chain (FTH), whereas Dmt1-IRE moderately elevates FTH and ferritin light-chain (FTL), with co-expression further enhancing FTL levels. Restoration of Dmt1 expression rescues ferritin levels, lysosomal activity, and NICD1 degradation while reducing oxidative stress and lipid peroxidation. Notably, Dmt1 deficiency decreases NICD1 binding to RBP-J{kappa}/CSL and its recruitment to Notch target gene promoters Hes1 and Hey1. Collectively, our findings demonstrate that Dmt1 regulates lysosomal function through iron homeostasis and that lysosomal dysfunction from Dmt1 loss impairs NICD1 degradation and disrupts Notch signaling, linking cellular iron metabolism and Notch pathway activity.

cell biology↗

bioRxiv2022

β1 integrin regulates alveolar epithelial cell differentiation following injury

During alveolar repair, alveolar type 2 (AT2) epithelial cell progenitors rapidly proliferate and differentiate into flat type 1 alveolar epithelial cells. Failure of normal alveolar repair mechanisms can lead to loss of alveolar structure (emphysema) or development of fibrosis, depending on the type and severity of injury. To test if {beta}1-containing integrins are required during repair following acute injury, we administered E. coli lipopolysaccharide (LPS) by intratracheal injection to mice with a post-developmental deletion of {beta}1 integrin in AT2 cells. While control mice recovered from LPS injury without structural abnormalities, {beta}1-deficient mice had more severe inflammation and developed emphysema. In addition, recovering alveoli were repopulated with an abundance of rounded epithelial cells co-expressing type 2, type 1, and mixed intermediate cell state markers, with few mature type 1 cells. {beta}1-deficient AT2 cells showed persistently increased proliferation after injury, which was blocked by inhibiting NF-{kappa}B activation in these cells. Lineage tracing experiments revealed that {beta}1-deficient AT2 cells failed to differentiate into mature type 1 alveolar epithelial cells. Together, these findings demonstrate that functional alveolar repair after injury with terminal alveolar epithelial differentiation requires {beta}1-containing integrins.

cell biology↗

bioRxiv2022

The unique ORF8 protein from SARS-CoV-2 binds to human dendritic cells and induces a hyper-inflammatory cytokine storm

The novel coronavirus pandemic, whose first outbreak was reported in December 2019 in Wuhan, China (COVID-19), is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Tissue damage caused by the virus leads to a strong immune response and activation of antigen-presenting cells, which can elicit acute respiratory distress syndrome (ARDS) characterized by the rapid onset of widespread inflammation, the so-called cytokine storm. In many viral infections the recruitment of monocytes into the lung and their differentiation to dendritic cells (DCs) are seen as a response to the viral infection. DCs are critical players in the development of the acute lung inflammation that causes ARDS. Here we focus on the interaction of the ORF8 protein, a specific SARS-CoV-2 open reading frame protein, with dendritic cells (DCs). We show that ORF8 binds to dendritic cells, causes a pre-maturation of differentiating DCs, and induces the secretion of multiple pro-inflammatory cytokines by these cells. In addition, we identified dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) as a possible interaction partner of ORF8 on dendritic cells. Blockade of ORF8 signaling leads to reduced production of IL-1{beta}, IL-6, IL-12p70, TNF-, MCP-1 (CCL2), and IL-10 by dendritic cells. Analysis of patient sera with high anti-ORF8 antibody titers showed that there was nearly no neutralization of the ORF8 protein and its function. Therefore, a neutralizing antibody that has the capacity of blocking the cytokine and chemokine response mediated by ORF8 protein might be an essential and novel additional step in the therapy of severe SARS-CoV-2 cases.

immunology↗

bioRxiv2022

Kidney collecting duct cells make vasopressin in response to NaCl induced hypertonicity

Vasopressin has traditionally been thought to be produced by the neurohypophyseal system and then released into the circulation where it regulates water homeostasis. The syndrome of inappropriate secretion of anti-diuretic hormone (vasopressin) raised the question if vasopressin could be produced outside of the brain and whether the kidney could be a source of vasopressin. We found that mouse and human kidneys expressed vasopressin mRNA. Using an antibody that detects the pre-pro-vasopressin, we found that immunoreactive pre-pro-vasopressin protein is found in mouse and human kidneys. Moreover, we found that murine collecting duct cells make biologically active vasopressin which increases in response to NaCl mediated hypertonicity, and that water restriction increases the abundance of kidney-derived vasopressin mRNA and protein expression in mouse kidneys. Thus, we provide evidence of biologically active production of kidney-derived vasopressin in kidney tubular epithelial cells.

physiology↗

bioRxiv2021

Reversal of the renal hyperglycemic memory by targeting sustained tubular p21 expression

A major therapeutic obstacle in diabetes mellitus is the metabolic or hyperglycemic memory: the persistence of impaired organ function despite improvement of blood glucose. Therapies reversing the hyperglycemic memory and thus improving already established organ-dysfunction are lacking, but urgently needed considering the increasing prevalence of diabetes mellitus worldwide. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with sustained induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, in several independent human samples and in in vitro models. Tubular p21 expression and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans, suggesting that p21 may be a biomarker indicating persistent ("memorized") kidney damage. Glucose-mediated p21 induction and tubular senescence were enhanced in mice with reduced levels of the disease resolving protease activated protein C (aPC). Mechanistically, glucose-induced and sustained tubular p21 expression is linked with demethylation of its promoter and reduced DNMT1 expression. aPC reverses already established p21 expression independent of its anticoagulant function through receptor signaling. Accordingly, new pharmacological approaches specifically mimicking aPC signaling (3K3A-aPC, parmodulin-2) enabled the reversal of glucose-mediated sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence contributes to the hyperglycemic memory but can be therapeutically targeted. Single sentence summaryaPC signaling targets persistent p21 expression and tubular senescence and reverses the hyperglycemic memory in diabetic kidney disease.

molecular biology↗

bioRxiv2021

Increased apoptotic priming of glioblastoma enables therapeutic targeting by BH3-mimetics

IDH wild-type glioblastoma (GBM) is the most prevalent malignant primary brain tumour in adults. GBM typically has a poor prognosis, mainly due to a lack of effective treatment options leading to tumour persistence or recurrence. Tackling this, we investigated the therapeutic potential of targeting anti-apoptotic BCL-2 proteins in GBM. Levels of anti- apoptotic BCL-xL and MCL-1 were consistently increased in GBM compared with non- malignant cells and tissue. Moreover, we found that relative to their differentiated counterparts, patient-derived GBM stem-like cells also displayed higher expression of anti- apoptotic BCL-2 family members. Surprisingly, high anti-apoptotic BCL-xL and MCL-1 expression correlated with heightened susceptibility of GBM to BCL-2 family protein- targeting BH3-mimetics. This is indicative of increased apoptotic priming. Indeed, GBM displayed an obligate requirement for MCL-1 expression in both tumour development and maintenance. Investigating this apoptotic sensitivity, we found that sequential inhibition of BCL-xL and MCL-1 led to robust anti-tumour responses in vivo, in the absence of overt toxicity. These data demonstrate that BCL-xL and MCL-1 pro-survival function is a fundamental prerequisite for GBM survival that can be therapeutically exploited by BH3- mimetics.

cancer biology↗