Biology subjects

Vigh, L.

Publications and source records attributed to Vigh, L..

3 recordsLinked to original sources

bioRxiv2024

Mild hyperthermia-induced thermogenesis in the endoplasmic reticulum defines stress response mechanisms

Previous studies reported that a mild, non-protein denaturing, fever-like temperature increase induced the unfolded protein response (UPR) in mammalian cells. Our dSTORM super-resolution microscopy experiments revealed that the master regulator of the UPR, the IRE1 (inositol-requiring enzyme 1) protein is clustered as a result of UPR activation in a human osteosarcoma cell line (U2OS) upon mild heat stress. Using ER thermo yellow, a temperature-sensitive fluorescent probe targeted to the endoplasmic reticulum (ER), we detected significant intracellular thermogenesis in mouse embryonic fibroblast (MEF) cells. Temperatures reached at least 8{degrees}C higher than the external environment (40{degrees}C), resulting in exceptionally high ER temperatures similar to those previously described for mitochondria. Mild heat-induced thermogenesis in the ER of MEF cells was likely due to the uncoupling of the Ca2+/ATPase (SERCA) pump. The high ER temperatures initiated a pronounced cytosolic heat shock response in MEF cells, which was significantly lower in U2OS cells in which both the ER thermogenesis and SERCA pump uncoupling were absent. Our results suggest that, depending on intrinsic cellular properties, mild hyperthemia-induced intracellular thermogenesis defines the cellular response mechanism, and determines the outcome of hyperthermic stress.

cell biology↗

bioRxiv2023

The Crystal Structure of the Hsp90-LA1011 Complex and the Mechanism by which LA1011 may Improve the Prognosis of Alzheimer's Disease.

Chaperone systems play a major role in the decline of cognition and contribute to neurological pathologies such as Alzheimers disease (AD). While such a decline may occur naturally with age or with stress or trauma, the mechanisms involved have remained elusive. The current models suggest that amyloid-{beta} (A{beta}) plaque formation leads to the hyperphosphorylation of tau by a Hsp90 dependent process that triggers tau neurofibrillary tangle formation and neurotoxicity. Several co-chaperones of Hsp90 can influence the phosphorylation of tau, including FKBP51, FKBP52 and PP5. In particular elevated levels of FKBP51 occur with age and stress and are further elevated in AD. Recently, the dihydropyridine, LA1011 was shown to reduce tau pathology and amyloid plaque formation in transgenic AD mice, probably through its interaction with Hsp90 although the precise mode of action is currently unknown. Here, we present a co-crystal structure of LA1011 in complex with a fragment of Hsp90. We show that LA1011 can disrupt binding of FKBP51, which might help to rebalance the Hsp90-FKBP51 chaperone machinery and provide a favourable prognosis towards AD. Clinically, this is highly significant, as AD is generally a disease affecting older patients, where slowing of disease progression could result in AD no longer being life limiting.

molecular biology↗

bioRxiv2019

Delineating the rules for structural adaptation of membrane-associated proteins to evolutionary changes in membrane lipidome

Membrane function is fundamental to life. Each species explores membrane lipid diversity within a genetically predefined range of possibilities. How membrane lipid composition in turn defines the functional space available for evolution of membrane-centered processes remains largely unknown. We address this fundamental question using related fission yeasts Schizosaccharomyces pombe and Schizosaccharomyces japonicus. We show that unlike S. pombe that generates membranes where both glycerophospholipid acyl tails are predominantly 16-18 carbons long, S. japonicus synthesizes unusual asymmetrical glycerophospholipids where the tails differ in length by 6-8 carbons. This results in stiffer bilayers with distinct lipid packing properties. Retroengineered S. pombe synthesizing the S. japonicus-type phospholipids exhibits unfolded protein response and downregulates secretion. Importantly, our protein sequence comparisons and domain swap experiments indicate that transmembrane helices co-evolve with membranes, suggesting that, on the evolutionary scale, changes in membrane lipid composition may necessitate extensive adaptation of the membrane-associated proteome.

cell biology↗