Stresszválasz: membrántól membránig = Stress response: from membrane to membrane

A 2005-ben befejezett munka során széles kisérleti háttere, különböző sejtes modellekre alapozva szisztematikus munkával igazoltuk az un "membrán szenzor" hipotézis univerzális érvényességét. A stresszfehérje (molekuláris chaperon) válasz sejt- és molekuláris hátterének egy teljesen új aspektusát tártuk fel, amikor is a stresszválasz primér jelképző funkcióját nem a proteotoxicitás, hanem a membránok lipidfázisa által kontrolált állapotváltozások látják el. A membránok lipid-lipid ill. lipid-fehérje kölcsönhatásaiban ("molekuláris kapcsolók") stressz (pld. magashőmérséklet) által kiváltott változásokat a membránok fehérje és lipidösszetételének ill. mikrodomén szintű finomszerveződésének szintjén követtük. Igazoltuk a stresszfehérjék lipidmediálta kölcsönhatásait. Kutatásaink újgenerációs gyógyszerek (pld. hidroximsavszármazékok) kifejlesztését alapozták meg. Ezek a stresszfehérje szintézis megfelelő kontrolljával olyan patológiás állapotok gyógyítását teszik lehetővé, mint a 2. típusú diabétesz, vagy a neurodegeneratív betegségek. | Based on broad experimental approaches and different cellular models in the course of the realization of this OTKA project we provided evidences on the universal validity of the ?membrane sensor? hypothesis. We explored a novel aspect of stress protein response by highlighting those conditions (mild heat stress, membrane defects in disease states, aging, etc.) under which the primary cellular stress sensing mechanism operates by subtle, lipid-phase controlled membrane alterations, rather than by massive proteotoxicity (severe stress). Membrane changes induced by various stress conditions (likely governed by lipid-lipid and lipid-protein interactions) were systematically monitored by real-time single molecule microscopy and coupled to the downstream signaling pathways, leading ultimately to hsp transcription. We have shown, that stress proteins are capable to transport and translocate to the lipid phase of membranes. Our investigations opened the door for the development of a new-generation of drugs. There mode of action is linked to the normalization of dysregulated stress protein response in disease states, like type2 diabetes or neurodegenerative diseases

Membrane-Associated Heat Shock Proteins in Oncology : From Basic Research to New Theranostic Targets

Heat shock proteins (HSPs) constitute a large family of conserved proteins acting as molecular chaperones that play a key role in intracellular protein homeostasis, regulation of apoptosis, and protection from various stress factors (including hypoxia, thermal stress, oxidative stress). Apart from their intracellular localization, members of different HSP families such as small HSPs, HSP40, HSP60, HSP70 and HSP90 have been found to be localized on the plasma membrane of malignantly transformed cells. In the current article, the role of membrane-associated molecular chaperones in normal and tumor cells is comprehensively reviewed with implications of these proteins as plausible targets for cancer therapy and diagnostics

Hsp70 interactions with membrane lipids regulate cellular functions in health and disease

Beyond guarding the cellular proteome the major stress inducible heat shock protein Hsp70 has been shown to interact with lipids. Non-cytosolic Hsp70 stabilizes membranes during stress challenges and, in pathophysiological states, facilitates endocytosis, counteracts apoptotic mechanisms, sustains survival pathways or represents a signal that can be recognized by the immune system. Disease-coupled lipid-associated functions of Hsp70 may be targeted via distinct subcellular localizations of Hsp70 itself or its specific interacting lipids. With a special focus on interacting lipids, here we discuss localization-dependent roles of the membrane-bound Hsp70 in the context of its therapeutic potential, particularly in cancer and neurodegenerative disease

Heat therapy shows benefit in patients with type 2 diabetes mellitus : a systematic review and meta-analysis

Type-2 diabetes mellitus (T2DM) is a common health condition which prevalence increases with age. Besides lifestyle modifications, passive heating could be a promising intervention to improve glycemic control. This study aimed to assess the efficacy of passive heat therapy on glycemic and cardiovascular parameters, and body weight among patients with T2DM.A systematic review and meta-analysis were reported according to PRISMA Statement. We conducted a systematic search in three databases (MEDLINE, Embase, CENTRAL) from inception to 19 August 2021. We included interventional studies reporting on T2DM patients treated with heat therapy. The main outcomes were the changes in pre-and post-treatment cardiometabolic parameters (fasting plasma glucose, glycated plasma hemoglobin, and triglyceride). For these continuous variables, weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated. Study protocol number: CRD42020221500.Five studies were included in the qualitative and quantitative synthesis, respectively. The results showed a not significant difference in the hemoglobin A1c [WMD -0.549%, 95% CI (-1.262, 0.164), p = 0.131], fasting glucose [WMD -0.290 mmol/l, 95% CI (-0.903, 0.324), p = 0.355]. Triglyceride [WMD 0.035 mmol/l, 95% CI (-0.130, 0.200), p = 0.677] levels were comparable regarding the pre-, and post intervention values.Passive heating can be beneficial for patients with T2DM since the slight improvement in certain cardiometabolic parameters support that. However, further randomized controlled trials with longer intervention and follow-up periods are needed to confirm the beneficial effect of passive heat therapy

Lipid-membrán iskola a Szegedi Biológiai Központban = Lipid-membrane school at the Biological Research Center

Tisztelegve az elhúnyt Farkas Tibor akadémikus emlékének, a Lipid-Membán Iskola a Szegedi Biológiai Központban minden tekintetben végrehajtotta a pályázatban tervezett feladatait, teljesítette misszióját. Képes volt a meglévő tudás valamint eszközállomány összefogására, koncentrált és hatékony kihasználására. A közös munka eredményeképpen számos, stratégiailag igen jelentős fejlesztés vált lehetővé. Nagy számú új, eredeti tudományos eredmény (köztük több review, ill. könyv) publikációjára került ill. kerül még sor a program lezárását követően. Törekvéseink fénypontját jelzik az egymolekula követésére alkalmas mikroszkópiás laboratórium (nanotechnológiai alapú membrán kutatóhely, SzBK) ill. az első hazai lipidomikai vertikum (SzTE, SzBK ) teljes kiépítése. Kiemelendő, hogy a program célkitűzésének megfelelően a kutatásba számos hallgatót vontunk be. Szakdolgozatok ill. PhD disszertációk születtek a pályázat támogatásával. Aktivitásunk egyértelmű nemzetközi elismeréseképpen 2006-ban Magyarországon kerül megrendezésre a Nemzetközi Lipidtudományi Konferencia (ICBL) kollégáink rendezésében, Vígh László elnökletével. A Lipid-Membrán Iskola szegedi résztvevői az alap- és alkalmazott lipid és membrán kutatási eredményeik, valamint a kiépült együttműködéseik alapján sikeresen részévé váltak a Dél-Alföldi Neurobiológiai Tudásközpontnak. | Saluting to the memory of late Tibor Farkas, the Lipid-Membrane School in the Szeged Biological Research Center successfully accomplished its major goals and fulfilled its mission. The school became capable for bringing together the preexisting knowledges and resources, by effectively concentrate and exploit them. As a result of the common and complementary efforts, several highly important and ambicious projects have been implemented. As a result of these, high number of new, original publications, reviews indicated the success. Amongst of our most remarkable achievements, we should mention the foundation of the nanotech based single molecule microscopy technique, allowing the real-time monitoring of most various lipid-membrane events (BRC). We are also proud, that the first Hungarian lipidomics lab can start soon its operation (SzTE, BRC). Several students participated in our activity: prepared diploma work and PhD thesis. Best highlighting our successful activity, our colleaques will organize the next International Congress of Lipid Sciences (ICBL), chaired by Laszlo Vigh. Based on their basic and applied research related activities and cooperation, most of the participants of the peresently terminated Szeged Lipid-Membrane School have joined successfully the Szeged Neurobiological Knowledge Center

Live cell superresolution-SIM imaging analysis of the intercellular transport of microvesicles and costimulatory proteins via nanotubes between immune cells

Halász, Henriett1,+, Ghadaksaz, Ali Reza1,2,+, Madarász, Tamás1, Huber, Krisztina2, Harami, Gábor3, Tóth, Eszter Angéla2, Osteikoetxea-Molnár, Anikó2, Kovács, Mihály3, Balogi, Zsolt5, Nyitrai, Miklós1,4, Matkó, János2,*, Szabó-Meleg, Edin

Mdm1/Snx13 is a novel ER–endolysosomal interorganelle tethering protein

Although endolysosomal trafficking is well defined, how it is regulated and coordinates with cellular metabolism is unclear. To identify genes governing endolysosomal dynamics, we conducted a global fluorescence-based screen to reveal endomembrane effector genes. Screening implicated Phox (PX) domain-containing protein Mdm1 in endomembrane dynamics. Surprisingly, we demonstrate that Mdm1 is a novel interorganelle tethering protein that localizes to endoplasmic reticulum (ER)-vacuole/lysosome membrane contact sites (MCSs). We show that Mdm1 is ER anchored and contacts the vacuole surface in trans via its lipid-binding PX domain. Strikingly, overexpression of Mdm1 induced ER-vacuole hypertethering, underscoring its role as an interorganelle tether. We also show that Mdm1 and its paralogue Ydr179w-a (named Nvj3 in this study) localize to ER-vacuole MCSs independently of established tether Nvj1. Finally, we find that Mdm1 truncations analogous to neurological disease-associated SNX14 alleles fail to tether the ER and vacuole and perturb sphingolipid metabolism. Our work suggests that human Mdm1 homologues may play previously unappreciated roles in interorganelle communication and lipid metabolism

Membrane fluidity matters: Hyperthermia from the aspects of lipids and membranes

Hyperthermia is a promising treatment modality for cancer in combination both with radio- and chemotherapy. In spite of its great therapeutic potential, the underlying molecular mechanisms still remain to be clarified. Due to lipid imbalances and 'membrane defects' most of the tumour cells possess elevated membrane fluidity. However, further increasing membrane fluidity to sensitise to chemo-or radiotherapy could have some other effects. In fact, hyperfluidisation of cell membrane induced by membrane fluidiser initiates a stress response as the heat shock protein response, which may modulate positively or negatively apoptotic cell death. Overviewing some recent findings based on a technology allowing direct imaging of lipid rafts in live cells and lipidomics, novel aspects of the intimate relationship between the 'membrane stress' of tumour cells and the cellular heat shock response will be highlighted. Our findings lend support to both the importance of membrane remodelling and the release of lipid signals initiating stress protein response, which can operate in tandem to control the extent of the ultimate cellular thermosensitivity. Overall, we suggest that the fluidity variable of membranes should be used as an independent factor for predicting the efficacy of combinational cancer therapies