Biology subjects

Haecker, G.

Publications and source records attributed to Haecker, G..

4 recordsLinked to original sources

bioRxiv2026

Crosstalk between Stromal cells and Macrophages Shapes Host Immunity to Mycobacteria

Granulomas are disease-defining heterocellular tissue structures in mycobacterial infections. They play a multifaceted role ranging from containing the pathogen to causing tissue destruction. Here, we established a mature peritoneal granuloma model in C57BL/6 mice to investigate the dynamic cell-cell interactions during mycobacterial infection, including long-term immune alterations in serous cavities as important sites of disease manifestation. We found that mycobacteria reside in stromal cells, which actively modulate the local tissue environment and shape macrophage responses, particularly through formation of chemokines and colony-stimulating factor 1. Chronic infection induces sustained reprogramming and diversification of stromal cells toward specialized, immune-like states, including active transfer of mycobacteria to macrophages and a pronounced interferon response. Consequently, stromal cells acquire immunoregulatory properties and support pathogen handling, monocyte recruitment and macrophage maturation, thereby playing a decisive role in granuloma formation and thus in the immune response to mycobacteria. HIGHLIGHTSO_LIA novel peritoneal mycobacterial infection model reveals heterocellular crosstalk in mature granulomas. C_LIO_LIMycobacterial infections persistently reshape immune architecture of serous cavities as important disease sites. C_LIO_LIStromal cells act as mycobacterial host cells and acquire immune effector functions. C_LIO_LIStromal cells co-organize the tissue host-pathogen interface by recruiting and directly communicating with bone marrow-derived monocytes. C_LI

immunology↗

bioRxiv2025

The Second Mitochondrial Activator of Caspases (SMAC) regulates growth, inflammation and mitochondrial integrity in cancer cells

SMAC is a mitochondrial intermembrane space protein, which is released during apoptosis and whose known function is antagonism of inhibitor of apoptosis proteins in the cytosol, to facilitate caspase activation. Recent data suggest that SMAC can also be released by sub-lethal signals in the apoptosis pathway, in the absence of cell death. We here explored potential functions of SMAC in non-apoptotic cells. We found that a portion of SMAC is spontaneously released into the cytosol in the absence of apoptosis, regulated by the BCL-2-family proteins BAX and BAK and the fission GTPase DRP1. In cancer cell lines, SMAC was required for the activation of caspases in lethal and non-lethal conditions, while this contribution to caspase-activation was much smaller in non-malignant fibroblast lines. In cells with high levels of cytosolic SMAC, SMAC deficiency reduced in vitro migration, invasion and anchorage-independent growth. SMAC-deficient cells further showed a reduced activity in interferon signalling, associated with reduced cytosolic presence of mitochondrial DNA and activation of the stimulator of interferon genes (STING), and SMAC expression levels correlated with interferon-induced genes in cancer data sets. We further found that SMAC can regulate mitochondrial morphology and integrity. Finally, high gene-expression of SMAC was associated with poor prognosis in patients of several cancer types. These results identify SMAC as a regulator of inflammation and growth behaviour of cancer cells. They further report a mitochondrial function of SMAC and demonstrate a role of SMAC in human cancer biology across several cancer entities.

cell biology↗

bioRxiv2025

Apoptotic caspases silence spontaneous innate immune signals by specifically cleaving activated mitochondrial antiviral signalling protein (MAVS)

Caspases-9, -3 and -7 are activated in the mitochondrial apoptosis pathway and lead to the apoptotic phenotype. Caspases also function to limit inflammation upon apoptotic mitochondrial permeabilization through degradation of the signalling proteins cGAS, MAVS and IRF3. Cells and mice lacking caspases have higher interferon levels and are resistant to viral infection. We report that in unstimulated, non-apoptotic cells caspase-3 functions to cleave specifically activated MAVS and very likely cGAS. In unstimulated HeLa cells, constitutive caspase-9- and -3-but not 7-dependent proteolytic events were observed. Inhibition of the mitochondrial apoptosis pathway in various healthy cells induced type I interferon (IFN I) through increased cGAS activity in the absence of changes to cGAS levels. We observed enhanced MAVS-dependent signals upon RIG-I-like helicase stimulation in the absence of BAX, caspase-9 or caspase-3 or upon caspase-inhibition. During activation, MAVS forms complexes, and blockade of mitochondrial apoptosis signalling increased complex abundance in unstimulated and stimulated cells. MAVS complexes were more sensitive to caspase-degradation than the monomer, and mutation of caspase-3-cleavage sites in MAVS spontaneously increased complex formation. Inhibition of voltage-dependent anion channel 1 (VDAC1) oligomerization blocked BAX/BAK- and caspase-regulated IFN induction, suggesting a stimulating role of leakage of mitochondrial DNA. We propose that low level, spontaneous activity of the mitochondrial apoptosis pathway, through specific caspase-3-mediated cleavage of only active signaling proteins, counteracts mitochondrial release of nucleic acids to reduce inflammation in the absence of infection. Caspase-3 therefore has a novel function in conformation- and activation-specific cleavage of substrates.

cell biology↗

bioRxiv2018

Checkpoint kinase 1 is essential for fetal haematopoiesis and hematopoietic stem cell survival

Checkpoint kinase 1 is critical for S-phase fidelity and preventing premature mitotic entry in the presence of DNA damage. Tumour cells have developed a strong dependence on CHK1 for survival and hence this kinase has developed into a popular drug-target. Chk1-deficiency in mice results in blastocyst death due to G2/M checkpoint-failure showing that it is an essential gene and may be difficult to target therapeutically without side-effects. Here, we show that chemical inhibition of CHK1 kills murine hematopoietic stem and progenitor cells (HSPCs) as well as human CD34+ HSPCs by the induction of BCL2-regulated but p53-independent apoptosis. Moreover, Chk1 is essential for stem cell survival and definite hematopoiesis in the mouse embryo. Remarkably though, cell death inhibition in hematopoietic stem cells (HSC) cannot restore blood cell formation in utero as Chk1 loss causes severe DNA damage that ultimately prevents HSC expansion. Our findings establish a previously unrecognized role for CHK1 in establishing hematopoiesis; they also suggest adverse effects of therapeutic CHK1-inhibtion, particularly under conditions forcing stem cells out of dormancy, such as chemotherapy-induced myelosuppression.

developmental biology↗