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Z. Török, T. Crui, B. Maresca, G. Schütz, F. Viana, L. Dindia, S. Piotto, M. Brameshuber, G. Balogh, M. Péter, A. Porta, A. Trapani, I. Gombos, A. Glatz, B. Gungor, B. Peksel, L. Vigh J., B. Csoboz, I. Horváth, M. Vijayan, P. Hooper, J. Harwood, L. Vigh:
"Plasma membranes as heat stress sensors: From lipid-controlled molecular switches to therapeutic applications";
Biochimica et Biophysica Acta, 1838 (2014), 1594 - 1618.

The classic heat shock (stress) response (HSR) was originally attributed to protein denaturation. However,
heat shock protein (Hsp) induction occurs in many circumstances where no protein denaturation is observed.
Recently considerable evidence has been accumulated to the favor of the "Membrane Sensor Hypothesis"
which predicts that the level of Hsps can be changed as a result of alterations to the plasma
membrane. This is especially pertinent to mild heat shock, such as occurs in fever. In this condition the sensitivity
of many transient receptor potential (TRP) channels is particularly notable. Small temperature
stresses can modulate TRP gating significantly and this is influenced by lipids. In addition, stress hormones
often modify plasma membrane structure and function and thus initiate a cascade of events, which may affect
HSR. The major transactivator heat shock factor-1 integrates the signals originating from the plasma
membrane and orchestrates the expression of individual heat shock genes.We describe how these observations
can be tested at the molecular level, for example, with the use of membrane perturbers and through
computational calculations. An important fact which now starts to be addressed is that membranes are
not homogeneous nor do all cells react identically. Lipidomics and cell profiling are beginning to address
the above two points. Finally, we observe that a deregulated HSR is found in a large number of important
diseases where more detailed knowledge of the molecular mechanisms involved may offer timely
Biochimica et Biophysica Acta 1838 (2014) 1594-1618
Abbreviations: AA, arachidonic acid; APAP, acetaminophen; aSMase, acid sphingomyelinase; ATP, adenosine triphosphate; BA, benzyl alcohol; BM, bimoclomol; CaMKII, calmodulin kinase
II; Cdase, ceramidase; CHO, Chinese hamster ovary; CHOL, cholesterol; CRA, crotonaldehyde; DAG, diacylglycerol; DMPC, 1,2-dimyristoyl-sn-glycero-3-phosphocholine; DPH, 1,6-
diphenyl-1,3,5-hexatriene; EGFR, epidermal growth factor receptor; ERK1/2, extracellular-signal-regulated kinase; FRET, fluorescence resonance energy transfer; GCS, glucosylceramide synthase;
GFP, green fluorescent protein; GFR, growth factor receptor; GlcCer, glucosylceramide; GPI, glycophosphatidylinositol; GR, glucocorticoid receptor; GSK3, glycogen synthase kinase-3;
HNE, 4-hydroxynonenal; HSF1, heat shock factor 1; HSP, heat shock protein; HSR, heat shock response; IP3, inositol trisphosphate; LB, luria broth; Ld, liquid disordered; Lo, liquid ordered;
LPA, lysophosphatidic acid; LPA, alpha lipoic acid; LPC, lysophosphatidylcholine; LPS, lysophosphatidylserine;MALDI,matrix-assisted laser desorption/ionization; MAPK, mitogen-activated
protein kinase; MBCD, methyl-β-cyclodextrin; MD, molecular dynamics; MPS, membrane physical state; mTOR, target of rapamycin; NADA, N-arachidonoyl-dopamine; NPN, 1-Nphenylnaphthylamine;
PhA, phenethyl alcohol; PHB, poly-(R)-3-hydroxybutyrate; PI3K, phosphatidylinositol-3-kinase; PI4P, phosphatidylinositol 4-phosphate; PIP2, phosphatidylinositol
4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-triphosphate; PKA, protein kinase A; PKC, protein kinase C; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; POPC,
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; POPE, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine; S1P, sphingosine-1-phosphate; SFA, saturated fatty acids; SGT,
glucosyltransferase; SK1, sphingosine kinase 1; SM, sphingomyelin; SPC, sphingosylphosphorylcholine; TIRF, total internal reflection fluorescence; TOCCSL, Thinning Out Clusters while
Conserving the Stoichiometry of Labeling; TRP, transient receptor potential channel; UFA, unsaturated fatty acids; YFP, yellow fluorescent protein
☆ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No DerivativeWorks License, which permits non-commercial use,
distribution, and reproduction in any medium, provided the original author and source are credited.
☆☆ This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.
⁎ Corresponding authors at: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, 6726-Szeged, Temesvari krt. 62, Hungary.
Tel.: +36 62 599 600/583.
E-mail addresses: tzsolt@brc.hu (Z. Török), vigh@brc.hu (L. Vigh).
0005-2736/$

Lipid raft TRP channel Heat shock response Stress hormone Cell-to-cell heterogeneity Lipidomics Membrane lipid therapy