Biology subjects

Fabrikova, D.

Publications and source records attributed to Fabrikova, D..

3 recordsLinked to original sources

bioRxiv2026

Aging-associated endo-lysosomal dysfunction drives inflammaging and neurodegeneration through the STING-IFN-I axis

All animals age. However, aging is a heterogeneous process and individual organisms age differently. Moreover, within the same organism, cells or organs do not age at the same time or speed. For instance, although neurodegeneration is a key trait of aging, neurological symptoms normally manifest long after multiple indicators of aging in peripheral tissues. The genetic determinants of aging remain poorly understood. Mutations in leucine-rich repeat kinase 2 (LRRK2) are major genetic risk factors for Parkinsons disease (PD). By analyzing PD patients and mice with LRRK2 gain of function mutation (LRRK2GoF), we demonstrate that PD is an accelerated aging disease characterized by systemic low-grade STING-dependent inflammation (inflammaging) that first manifests in the periphery then disrupts the blood brain barrier and progresses to the brain resulting in neurodegeneration. Mechanistically, we demonstrate that a primary consequence of aging or Lrrk2GoF is endolysosomal decline. This results in the cytosolic build-up of extraneous self-DNA and subsequent shedding of DNA-containing extracellular vesicles thereby triggering the cGAS- STING pathway cell-intrinsically and intercellularly in distant host cells. This study unveils the cGAS-STING pathway and LRRK2GoF as key determinants and potential targets for preventive or therapeutic strategies against accelerated aging, inflammaging and neurodegeneration.

immunology↗

bioRxiv2022

Lung macrophages utilize cathepsin K-dependent phagosomal machinery to degrade intracellular collagen

Resident tissue macrophages (RTMs) are organ-specialized phagocytes responsible for the maintenance and protection of tissue homeostasis. It is well established that tissue diversity is reflected by the heterogeneity of RTMs origin and phenotype. However, much less is known about tissue-specific phagocytic and proteolytic macrophage functions. Here, using quantitative proteomics approach, we identify cathepsins as key determinants of phagosome maturation in primary peritoneal, lung and brain resident macrophages. The data further uncover cathepsin K (CtsK) as a molecular marker for lung phagosomes required for intracellular protein and collagen degradation. Pharmacological blockade of CtsK activity diminished phagosomal proteolysis and collagenolysis in lung resident macrophages. Furthermore, pro-fibrotic TGF-{beta} negatively regulated CtsK-mediated phagosomal collagen degradation independently from classical endocytic proteolytic pathways. In humans, phagosomal CtsK activity was reduced in COPD lung macrophages and non-COPD lung macrophages exposed to cigarette smoke extract. Taken together, this study provides a comprehensive map of how peritoneal, lung and brain tissue environment shapes phagosomal composition, revealing CtsK as a key molecular determinant of lung phagosomes contributing to phagocytic collagen clearance in lungs.

cell biology↗

bioRxiv2021

The E3 ligase RNF115 regulates phagosome maturation and host response to bacterial infection

Phagocytosis is a key process in innate immunity and homeostasis. After uptake, newly formed phagosomes mature by acquisition of endo-lysosomal enzymes. Macrophage activation by interferon-gamma (IFN-{gamma}) increases microbicidal activity, but delays phagosomal maturation by an unknown mechanism. Using quantitative proteomics, we show that phagosomal proteins harbour high levels of typical and atypical ubiquitin chain types. Moreover, phagosomal ubiquitylation of vesicle trafficking proteins is substantially enhanced upon IFN-{gamma} activation of macrophages, suggesting a role in regulating phagosomal functions. We identified the E3 ubiquitin ligase RNF115, which is enriched on phagosomes of IFN-{gamma} activated macrophages, as an important regulator of phagosomal maturation. Loss of RNF115 protein or ligase activity enhanced phagosomal maturation and increased cytokine responses to bacterial infection, suggesting that both innate immune signalling from the phagosome and phagolysosomal trafficking are controlled through ubiquitylation. RNF115 knock-out mice show less tissue damage in response to S. aureus infection, indicating a role of RNF115 in inflammatory responses in vivo. In conclusion, RNF115 and phagosomal ubiquitylation are important regulators of innate immune functions during bacterial infections.

biochemistry↗