Biology subjects

Toth, S.

Publications and source records attributed to Toth, S..

5 recordsLinked to original sources

bioRxiv2026

SERCA is a host target of the SARS-CoV-2 envelope protein linking calcium homeostasis to autophagy

The SARS-CoV-2 envelope (E) protein is a virulence factor that remodels host endomembranes, but mechanisms remain incompletely understood. We recently demonstrated that E protein interacts with and inhibits the sarco/endoplasmic reticulum Ca2-ATPase (SERCA), disrupting ER calcium homeostasis. Here, we investigated how this perturbation affects autophagy-associated membrane organization. E protein expression induced lipidated LC3 accumulation and enlarged p62-positive structures, consistent with dysregulated autophagic turnover. Although E protein partially colocalized with LC3 and p62, enlarged p62-positive structures were also observed in cells retaining the reticular ER distribution of E protein, indicating that their formation does not require association with E protein or ER reorganization. E protein also increased the association of p62-positive structures with lysosomes without altering lysosome abundance. Pharmacological SERCA activation attenuated E protein-induced remodeling of autophagy-associated structures, demonstrating that SERCA inhibition contributes to these alterations. Together, our findings establish SERCA-dependent ER calcium homeostasis as a host pathway linking E protein expression to remodeling of autophagy-associated membrane compartments, providing a mechanistic framework for how the SARS-CoV-2 E protein promotes ER membrane remodeling associated with coronavirus replication.

cell biology↗

bioRxiv2024

The calcium pump PMCA4b promotes epithelial cell polarization and lumen formation

Loss of epithelial cell polarity and tissue disorganization are hallmarks of carcinogenesis, in which Ca2+ signaling plays a significant role. Here we demonstrate that the plasma membrane Ca2+ pump PMCA4 (ATP2B4) is downregulated in luminal breast cancer, and this is associated with shorter relapse-free survival in patients with luminal A and B1 subtype tumors. Using the MCF-7 breast cancer cell model we show that PMCA4 silencing results in the loss of cell polarity while a forced increase in PMCA4b expression induces cell polarization and promotes lumen formation in 2D and 3D cell cultures. We identify Arf6 as a novel regulator of PMCA4b endocytic recycling essential for PMCA4 regulated lumen formation. Silencing of the single pmca gene in Drosophila melanogaster larval salivary gland destroys lumen morphology suggesting a conserved role of PMCAs in lumen morphogenesis. Our findings point to a novel role of PMCA4 in controlling epithelial cell polarity, and in the maintenance of normal glandular tissue architecture.

cell biology↗

bioRxiv2023

Redox-dependent condensation and cytoplasmic granulation by human ssDNA binding protein 1 delineate roles in oxidative stress response

Human single-stranded DNA binding protein 1 (hSSB1/NABP2/OBFC2B) plays central roles in the repair of DNA breaks and oxidized DNA lesions. Here we show that hSSB1 undergoes liquid-liquid phase separation (LLPS) that is redox-dependent and requires the presence of single-stranded DNA or RNA, features that are distinct from those of LLPS by bacterial SSB. hSSB1 nucleoprotein droplets form under physiological ionic conditions, in response to treatment resulting in cellular oxidative stress. hSSB1s intrinsically disordered region (IDR) is indispensable for LLPS, whereas all three cysteine residues of the oligonucleotide/oligosaccharide-binding (OB) fold are necessary to maintain redox-sensitive droplet formation. Proteins interacting with hSSB1 show selective enrichment inside hSSB1 droplets, suggesting tight content control and recruitment functions for the condensates. While these features appear instrumental for genome repair, we also detected hSSB1 condensates in the cytoplasm in response to oxidative stress in various cell lines. hSSB1 condensates colocalize with stress granules, implying unexplored extranuclear roles in cellular stress response. Our results suggest novel, condensation-linked roles for hSSB1, linking genome repair and cytoplasmic defense.

biochemistry↗

bioRxiv2021

A novel PSII photosynthetic control is activated in anoxic cultures of green algae

Photosynthetic green algae face an ever-changing environment of fluctuating light as well as unstable oxygen levels, which via the production of free radicals constantly challenges the integrity of the photosynthetic complexes. To face such challenges, a complex photosynthetic control network monitors and tightly control the membrane redox potential. Here, we show that not only that the photosynthetic control set the rate limiting step of photosynthetic linear electron flow, but also, upon its ultimate dissipation, it triggers intrinsic alternations in the activity of the photosynthetic complexes. These changes have a grave and prolonged effect on the activity of photosystem II, leading to a massive 3-fold decrease in its electron output. We came into this conclusion via studying a variety of green algae species and applying advance mass-spectrometry and diverse spectroscopic techniques. Our results shed new light on the mechanism of photosynthetic regulation, and provide new target for improving photosynthesis.

plant biology↗

bioRxiv2019

A Sex-Specific Switch in Platelet Receptor Signaling Following Myocardial Infarction

BACKGROUNDA Sex-specific, personalized approach to anti-platelet therapy may be important in patients with myocardial infarction (MI).\n\nOBJECTIVESOur goal was to determine whether platelets activate differently in healthy men and women compared to following MI.\n\nMETHODSBlood was obtained from healthy subjects or patients presenting acutely with ST-segment Elevation Myocardial Infarction (STEMI) and non-ST Segment Elevation Myocardial Infarction (NSTEMI). Platelet function through surface receptor activation was examined in healthy subjects, in patients with MI, and in age- and strain-matched mice before and after MI. Multivariate regression analyses revealed clinical variables associated with platelet receptor sensitivity at the time of MI.\n\nRESULTSPlatelets from healthy women are dose-dependently more active compared to men, particularly through the platelet thromboxane signaling pathway (7.8-fold increase in women vs. 3.0-fold in men, P=0.02). At the time of MI, platelet activation through surface protease-activated receptor 1 (PAR1) was less in women than men (3.5-fold vs. 8.5-fold, respectively, P=0.0001). Multivariate regression analyses revealed male sex (P=0.04) and NSTEMI (P=0.003) as independent predictors of enhanced platelet PAR1 signaling at the time of MI. Similar to humans, healthy female mice showed preferential thrombin-mediated platelet activation compared to male mice (8.7-fold vs. 4.8-fold, respectively; P<0.001). In the immediate post-MI environment, male mice showed preferential thrombin-mediated platelet activation compared to female mice (12.4-fold vs. 5.5-fold, respectively; P<0.001).\n\nCONCLUSIONSThese results outline a previously unrecognized sex-dependent platelet phenotype where inhibition of thrombin signaling in the peri-MI environment--particularly in males--may be an important consideration.\n\nCONDENSED ABSTRACTPreclinical studies evaluating anti-platelet drugs are generally conducted in platelets isolated from healthy individuals. Growing evidence suggests changes in platelet signaling properties in certain disease conditions compared to healthy platelets may alter the response to anti-platelet medications. This investigation revealed that platelets from men and women who are healthy and following MI signal differently, particularly through thromboxane and PAR1 receptors. This effect was especially noted in patients with NSTEMI compared to STEMI. These observations raise the possibility of considering a sex-specific anti-platelet regimen for males and females in atheroembolic vascular diseases such as NSTEMI.

molecular biology↗