Biology subjects

Khoronenkova, S. V.

Publications and source records attributed to Khoronenkova, S. V..

3 recordsLinked to original sources

bioRxiv2026

TCF25 emerges as a cytoplasmic regulator of GPRASP2 stability

TCF25 is a conserved eukaryotic protein whose cellular localisation and functional context remain poorly understood. Here, we show that under basal conditions, TCF25 is predominantly cytoplasmic across several human cell types, with a digitonin-resistant perinuclear pool indicative of association to membrane-linked components. Exploration of TCF25's proximal network using proximity labelling further supports enrichment of cytoplasmic and intracellular membrane-associated proteins. Guided by the analysis of public datasets and the proximal proteome data, we show that TCF25 associates with G-protein coupled receptor-associated sorting protein, GPRASP2, and maintains its basal abundance by protecting it from proteasomal degradation. Using structural modelling, we identify a putative interaction interface between the two proteins, involving two closely-spaced helices in the C terminal region of TCF25 that dock to the helical repeat segment of GPRASP2. Consistent with this prediction, deletion of TCF25 amino acids 604-664 disrupted the relationship between TCF25 and GPRASP2. Together, these findings establish a cytoplasmic, membrane-proximal context for TCF25 and identify a C-terminal tract required for its association with GPRASP2. These findings implicate TCF25 in regulating GPRASP2 stability, providing a framework for investigating its role in cellular homeostasis and disease.

biochemistry↗

bioRxiv2023

The cGAS-STING pathway regulates microglial chemotaxis in genome instability

Defective DNA damage signalling and repair is a hallmark of age-related and genetic neurodegenerative disease. One mechanism implicated in disease progression is DNA damage-driven neuroinflammation, which is largely mediated by tissue-resident immune cells, microglia. Here, we utilise human microglia-like cell models of persistent DNA damage and ATM kinase deficiency to investigate how genome instability shapes microglial function. We demonstrate that upon DNA damage the cytosolic DNA sensing cGAS-STING axis drives chronic inflammation and a robust chemokine response, exemplified by production of CCL5 and CXCL10. Transcriptomic analyses revealed that cell migratory pathways were highly enriched upon IFN-{beta} treatment of human iPSC-derived microglia, indicating that the chemokine response to DNA damage mirrors type I interferon signalling. Furthermore, we find that STING deletion leads to a defect in microglial chemotaxis under basal conditions and upon ATM kinase loss. Overall, this work provides mechanistic insights into cGAS-STING-dependent neuroinflammatory mechanisms and consequences of genome instability in the central nervous system.

cell biology↗

bioRxiv2021

Persistent DNA damage promotes microglial dysfunction in Ataxia-telangiectasia

The autosomal recessive genome instability disorder Ataxia-telangiectasia, caused by mutations in ATM kinase, is characterised by the progressive loss of cerebellar neurons. We find that DNA damage associated with ATM loss results in dysfunctional behaviour of human microglia, immune cells of the central nervous system. Microglial dysfunction is mediated by the pro-inflammatory RELB/p52 non-canonical NF-{kappa}B transcriptional pathway and leads to excessive phagocytic clearance of neurites. Pathological phagocytosis of neuronal processes by microglia has also been observed in multiple sclerosis, Alzheimers and progranulin deficiency, suggesting a common mechanism that promotes neuronal damage. Activation of the RELB/p52 pathway in ATM-deficient microglia is driven by persistent DNA damage and is dependent on the NIK kinase. These results provide insights into the underlying mechanisms of aberrant microglial behaviour in Ataxia-telangiectasia, potentially contributing to neurodegeneration.

cell biology↗