Biology subjects

Otto, F.

Publications and source records attributed to Otto, F..

8 recordsLinked to original sources

bioRxiv2026

Form IF Rubiscos include highly active, specific, and small subunit-independent enzymes.

Plant-type (Form I) Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) suffers from inherent catalytic trade-offs and a strong dependency on other proteins--including an essential small subunit (SSU) and auxiliary chaperones--for assembly, constraining the enzymes evolutionary and engineering potential. Here, we investigated representatives from the newly discovered clade Form IF. These enzymes do not require specific chaperones to form functional complexes, exhibit high CO2-specificities (SC/O [~]50) while maintaining high turnover rates (up to kcat [~]11 s-1). Remarkably, two Form IF representatives (IF-1/IF-2) lost the dependency on the SSU and assemble into homo-octameric complexes without their cognate SSUs. While the SSU is not necessary for catalysis, its addition improves both activity and specificity in IF-1/IF-2. Our results show that complexity is actually not required to achieve highly active, specific and functional Rubisco variants--and that this complexity can even be reverted--which challenges our current thinking on the evolution and catalytic mechanism of Rubisco.

biochemistry↗

bioRxiv2026

O-GlcNAcylation and low glycolysis underpin Th2 polarization by dendritic cells

Activation of dendritic cells (DCs) is dependent on rewiring of their cellular metabolism. However, the metabolic requirements for DCs to prime T helper 2 (Th2) responses are still poorly understood. Using unbiased transcriptomics and non-targeted metabolomics we find that helminth antigen-conditioned human DCs suppress glycolysis while increasing hexosamine biosynthesis to fuel protein O-GlcNAcylation. Functionally, glycolytic inhibition of DCs selectively enhanced, while blocking O-GlcNAcylation impaired, Th2-priming capacity. In helminth infection and allergic challenge, Th2 responses were also attenuated in vivo in mice with specific deletion of O-GlcNAc Transferase (OGT) in CD11c-expressing cells. Mechanistically, through proteomic analysis and functional validation, we identified O-GlcNAcylation as a critical negative regulator of immune synapse formation by controlling cytoskeletal organization via Fascin-1 and Zyxin, thereby dampening TCR signalling to promote Th2 polarization. Altogether we reveal a novel metabolic program in DCs that governs Th2 polarization, that could potentially be harnessed to treat type 2 mediated inflammatory diseases.

immunology↗

bioRxiv2026

O-GlcNAcylation drives macrophage IL-4 responsiveness and tissue residency through metabolic and cell cycle calibration

The metabolic requirements for macrophage IL-4 polarization remain contentious, while immunometabolic studies of tissue resident macrophages are still sparse. Hexosamine biosynthesis has gained attention regarding its immune regulatory potential via downstream O-GlcNAcylation. Here we identify protein O-GlcNAcylation as a requirement for IL-4 polarization in vitro and proliferative expansion in vivo during cytokine challenge or infection. We further show that O-GlcNAcylation is critical for controlling tissue residency. By enforcing metabolic and cell cycle quiescence during differentiation, O-GlcNAcylation is needed for adult monocytes to establish a long-live residency program. In this context, its absence leads to perpetual DNA vulnerability and damage via reactive oxygen species, resulting in a senescent-like state poised for cell death. Conversely, long-lived populations instead require O-GlcNAcylation for self-renewal and inflammatory expansion. Our findings altogether suggest O-GlcNAcylation, fueled by hexosamine biosynthesis, serves as a central metabolic rheostat for resident macrophage formation and maintenance during homeostasis and disease.

immunology↗

bioRxiv2025

Totum-448, a polyphenol-rich plant extract, decreases hepatic steatosis and inflammation in diet-induced MASLD mice

The increasing prevalence of obesity-driven metabolic dysfunction-associated steatotic liver disease (MASLD) urges the development of new therapeutic strategies. Totum-448 is a unique patented combination of polyphenol-rich plant extracts designed to reduce hepatic steatosis, a risk factor for steatohepatitis and type 2 diabetes. In this study, we investigated the effects of Totum-448 on metabolic homeostasis and steatohepatitis in diet-induced MASLD mice. For this purpose, male C57Bl6/J mice were fed a high-fat diet in combination with sucrose-containing drinking water for 12 weeks, followed by diet supplementation with or without Totum-448 for 4 weeks. Body weight/composition, caloric intake, plasma parameters and whole-body glucose tolerance were measured throughout the study and fecal microbiota composition was determined by 16S sequencing. Hepatic steatosis, transcriptomic/lipidomic profiles and immune cell composition were assessed by histological/biochemical assays, RNA sequencing, MS-based lipidomics, and spectral flow cytometry. We found that Totum-448 significantly lowered hyperinsulinemia and systemic glucose intolerance in MASLD mice without affecting body weight, fat mass, calorie intake, feces production or fecal microbiota composition. Furthermore, a decrease in liver MASLD activity score and macrovesicular steatosis, hepatic triglycerides and cholesterol contents, and plasma alanine aminotransferase levels were observed. Totum-448 also reduced the liver inflammatory and pro-fibrotic transcriptomic signatures and decreased both MASLD-induced loss in tissue-resident Kupffer cells and recruitment of monocyte-derived pro-inflammatory macrophages. Altogether, Totum-448 reduces hepatic steatosis and inflammation in insulin-resistant, steatotic, obese mice, a dual effect that likely contributes to improved whole-body metabolic homeostasis. Supplementation with Totum-448 may therefore constitute a promising novel nutritional approach for MASLD patients.

physiology↗

bioRxiv2023

AMPK activation induces RALDHhigh tolerogenic dendritic cells through rewiring of glucose and lipid metabolism

It is well known that dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. The AMP-activated kinase (AMPK) is a central nutrient and energy sensor whose activation promotes catabolism while inhibiting ATP-consuming anabolic pathways. Yet the contribution of AMPK activation to DC tolerogenicity remains unknown. Here, we show that AMPK activation renders human monocyte-derived DCs tolerogenic as evidenced by an enhanced ability to drive differentiation of regulatory T cells, a process dependent on increased RALDH activity. This is accompanied by a number of distinct metabolic changes, in particular increased breakdown of glycerophospholipids, enhanced mitochondrial fission-dependent fatty acid oxidation, and upregulated glucose catabolism. This metabolic rewiring is functionally important as we found interference with these metabolic processes to reduce to various degrees AMPK-induced RALDH activity as well as the tolerogenic capacity of moDCs. Altogether, our findings reveal a key role for AMPK signaling in shaping DC tolerogenicity, and suggest that AMPK may serve as new target to direct DC-driven immune responses in therapeutic settings.

immunology↗

bioRxiv2023

Metabolic sensor AMPK licenses CD103+ dendritic cells to induce Treg responses

Dendritic cells (DCs) play a crucial role in promoting tolerance through priming of regulatory T cells (Treg). Several studies indicate DC tolerogenicity is dependent on catabolic metabolism. However, the role of AMP-activated Kinase (AMPK), a key energy and nutrient sensor driving catabolic metabolism, in this process is unclear. We found that human retinoic acid-induced tolerogenic CD103+ DCs (RA-DCs) display increased AMPK signaling. Interestingly, RA-DCs, but not vitamin-D3- or dexamethasone-induced tolerogenic DCs, required AMPK for Treg induction. Mechanistically, AMPK underpinned RA-driven tolerogenicity by promoting RALDH activity in a FoxO3-dependent manner. Correspondingly, mice deficient for AMPK in DCs (CD11c{Delta}AMPK1) harbored reduced frequencies of intestinal CD103+CD11b+ DCs with impaired RALDH activity. Importantly, upon infection with parasitic worm Schistosoma mansoni, that elicits strong Th2 and Treg responses, CD11c{Delta}AMPK1 mice showed a defect in Treg accumulation and concomitantly, displayed an impaired ability to control Type 2 immunity-driven granulomatous inflammation against the parasite eggs. Together, our findings identify AMPK as a key regulator of tolerance by CD103+ DCs. SummaryDendritic cells (DCs) are critical for inducing tolerance. However, how metabolic cues control their tolerogenicity is still poorly understood. Patente et al demonstrate that AMPK is crucial for Treg induction by retinoic acid-primed tolerogenic CD103+ DCs.

immunology↗

bioRxiv2021

LKB1 signalling in dendritic cells controls whole-body metabolic homeostasis by limiting T helper 17 priming

Obesity-associated metaflammation drives the development of insulin resistance and type 2 diabetes, notably through modulating innate and adaptive immune cells in metabolic organs. The nutrient sensor liver kinase B1 (LKB1) has recently been shown to control cellular metabolism and T cell priming functions of dendritic cells (DCs). Here, we report that hepatic DCs from high-fat diet (HFD)-fed obese mice display increased LKB1 phosphorylation and that LKB1 deficiency in DCs (CD11c{Delta}LKB1) worsened HFD-driven hepatic steatosis, systemic insulin resistance and glucose intolerance. Loss of LKB1 in DCs was associated with increased cellular expression of Th17-polarizing cytokines and increased hepatic CD4+ IL-17A+ Th17 cells in HFD-fed mice. Importantly, IL-17A neutralization rescued metabolic perturbations in HFD-fed CD11c{Delta}LKB1 mice. Mechanistically, disrupted metabolic homeostasis was independent of the canonical LKB1-AMPK axis. Instead, we provide evidence for involvement of the AMPK-related salt-inducible kinase(s) in controlling Th17-polarizing cytokine expression in LKB1-deficient DCs. Altogether, our data reveal a key role for LKB1 signalling in DCs in protection against obesity-induced metabolic dysfunctions by limiting hepatic Th17 differentiation.

immunology↗

bioRxiv2020

The helminth glycoprotein omega-1 improves metabolic homeostasis in obese mice through type-2 immunity-independent inhibition of food intake

Type 2 immunity plays an essential role in the maintenance of metabolic homeostasis and its disruption during obesity promotes meta-inflammation and insulin resistance. Infection with the helminth parasite Schistosoma mansoni and treatment with its soluble egg antigens (SEA) can induce a type 2 immune response in metabolic organs and improve insulin sensitivity and glucose tolerance in obese mice, yet a causal relationship remains unproven. Here, we investigated the effects and underlying mechanisms of the T2 ribonuclease omega-1 (ω1), one of the major S. mansoni immunomodulatory glycoproteins, on metabolic homeostasis. Male C57Bl6/J mice were fed a high-fat diet for 12 weeks followed by bi-weekly injection of SEA, ω1 or vehicle for 4 additional weeks. Whole-body metabolic homeostasis and energy expenditure were assessed by glucose/insulin tolerance tests and indirect calorimetry, respectively. Tissue-specific immune cell phenotypes were determined by flow cytometry. We show that treatment of obese mice with plant-produced recombinant ω1, harboring similar glycan motifs as present on the native molecule, decreased body fat mass and improved systemic insulin sensitivity and glucose tolerance in a time-and dose-dependent manner. This effect was associated with an increase in white adipose tissue (WAT) type 2 T helper cells, eosinophils and alternatively-activated macrophages, without affecting type 2 innate lymphoid cells. In contrast to SEA, the metabolic effects of ω1 were still observed in obese STAT6-deficient mice with impaired type 2 immunity, indicating that its metabolic effects are independent of the type 2 immune response. Instead, we found that ω1 inhibited food intake, without affecting locomotor activity, WAT thermogenic capacity or whole-body energy expenditure, an effect also occurring in leptin receptor-deficient obese and hyperphagic db/db mice. Altogether, we demonstrate that while the helminth glycoprotein ω1 can induce type 2 immunity, it improves whole-body metabolic homeostasis in obese mice by inhibiting food intake via a STAT6-independent mechanism.Author summary The obesity-induced chronic low-grade inflammation, notably in adipose tissue, contributes to insulin resistance and increased risk of type 2 diabetes. We have previously shown that infection with parasitic helminth worms was associated with protection against obesity-related metabolic dysfunctions both in mice and humans. We have also reported that treatment of obese mice with an extract of Schistosoma mansoni eggs (SEA) improves insulin sensitivity and glucose tolerance, a beneficial effect that was associated with a helminth-specific type 2 immune response in metabolic organs. Here, we studied the effects of omega-1 (ω1), a single immunomodulatory molecule from SEA, on metabolic health in obese mice, and investigated the role of the host immune response elicited. We found that ω1 induced a helminth-characteristic type 2 immune response in adipose tissue and improved both insulin sensitivity and glucose tolerance in obese mice. Yet, in contrast to SEA, ω1’s immunomodulatory properties were dispensable for its metabolic effects. Instead, we show that ω1 inhibited food intake, a feature accounting for most of the improvements in metabolic health. Together, our findings indicate that helminth molecules may improve metabolic health through multiple distinct mechanisms, and further characterization of such molecules could lead to new therapeutic strategies to combat obesity.List of abbreviationsAAMAlternatively activated macrophageALATAlanine aminotransferaseBATBrown adipose tissueDCDendritic cellEEEnergy expenditureGTTGlucose tolerance testHEKHuman embryonic kidneyHFDHigh-fat dietHOMA-IRHomeostatic model assessment of insulin resistanceIFN-γInterferon gammaILInterleukinILCInnate lymphoid cellITTInsulin tolerance testLBMLean body massLFDLow-fat dietNAFLDNon-alcoholic fatty liver diseaseNASHNon-alcoholic steatohepatitispLeX-ω1Recombinant omega-1 from LeX-glyco-engineered Nicotiana benthamiana plantsPMAPhorbol myristate acetatepWT-ω1Recombinant omega-1 from wild-type N. benthamiana plantsSEASchistosoma mansoni soluble egg antigensSTATSignal transducer and activator of transcriptionSVFStromal vascular fractionThT helperTNFTumor necrosis factorUCP1Uncoupling protein 1WATWhite adipose tissueWTWild-typeView Full Text

immunology↗