Biology subjects

Jakob, J.

Publications and source records attributed to Jakob, J..

3 recordsLinked to original sources

bioRxiv2026

Extracellular protein catabolism drives regulated nitrogen handling and ammonia buffering in acute myeloid leukemia

Acute myeloid leukemia (AML) cells exhibit pronounced metabolic plasticity, yet how amino acid supply is coordinated to sustain leukemic metabolism remains poorly understood. Here, we show that AML cells catabolize extracellular proteins as a major source of amino acids through lysosomal degradation of albumin. This proteocatabolic activity supports anabolic processes and mitochondrial energy production and establishes a regulated, high-throughput regime of primary nitrogen-containing metabolites (nitrogen regimen). Sustained proteocatabolism inevitably generates ammonia, and we find elevated ammonia concentrations in bone marrow plasma from newly diagnosed AML patients that decline with effective induction therapy. Using metabolomics, isotope tracing and targeted genetic and pharmacological manipulations, we identify glutamate-ammonia ligase (GS/GLUL) as a central enzyme that buffers proteocatabolism-derived ammonia by stabilizing intracellular nitrogen homeostasis. Loss of GS function limits sustainable nitrogen handling capacity, thereby impairing leukemic proliferation and delaying disease progression in vivo. Together, our findings define extracellular protein catabolism as a regulating nitrogen management strategy in AML and reveal GS as a capacity-defining vulnerability of proteocatabolic growth.

cancer biology↗

bioRxiv2026

Crystal structure of E. coli Nissle 1917 flagellin reveals novel features that modulate bacterial motility but not TLR5 recognition

The probiotic E. coli Nissle 1917 (EcN) strain is known to promote intestinal homeostasis via flagellin, the protomer of its motility apparatus, the flagellum. The flagellin of EcN shows atypical features, namely a hypervariable region (HVR), whose structure and significance have remained elusive. We therefore determined the crystal structure of the E. coli Nissle 1917 flagellin FliC at a resolution of 1.2 [A] which revealed an unusual domain architecture: the canonical D1 domain was found connected by an extended linker to an extensive HVR whose D2, D3 and D4 domains form an outer domain (OD) which surrounds the filament core comprised of conserved domains D0-D1. Using both recombinant proteins and gene-edited EcN strains expressing mutant flagellins, the functional requirement for these unique features was subsequently studied for effects on immune recognition on intestinal epithelial and immune cells, as well as on flagellar protein expression, assembly and bacterial motility. While human and mouse TLR5 immune recognition of flagellar proteins or intact bacteria was only moderately affected by removal of linker or D4, especially linker removal reduced protein stability and bacterial motility in both soft agar and liquid media swimming assays. Interestingly, depending on the environment, D4 or HVR removal had different effects on motility and surface structure. Finally, a site-directed mutagenesis approach highlighted that loss of TLR5 recognition strictly entails loss of motility but not vice versa. Our data indicate that specific HVRs/OD might be relevant for motility of E. coli Nissle 1917 in specialized environments, but not for immune recognition. Moreover, we find mutational tolerance is greater for immune recognition than for motility, providing new insights into bacterial adaptation to the host environment.

microbiology↗

bioRxiv2023

Monocarboxylate transporters facilitate succinate uptake into brown adipocytes

Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole body energy expenditure, counteracts obesity, and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion of it present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import, however other members of the MCT family can partially compensate and fulfill this role in the absence of MCT1. In mice, we show that acute pharmacological inhibition of MCT1 and 2 decreases succinate uptake into BAT. Conversely, congenital genetic depletion of MCT1 alone has little effect on BAT succinate uptake, indicative of additional transport mechanisms with high capacity in vivo. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.

cell biology↗