Plasma membranes as heat stress sensors: From lipid-controlled molecular switches to therapeutic applications

Abstract

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 opportunities for clinical interventions and new, innovative drug treatments. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

The role of small GTPase Rac1 in stress signaling

“…Besides their roles in the structural organization of PMs, different membrane lipids can be metabolized and give rise to signaling molecules in response to stimuli and thus alter the gene expression of HSPs (Vigh et al 2007;Balogh et al 2013;Török et al 2014). According to lipid analysis results, heat stress stimulates the accumulation of Chol and Cer levels while SM levels are slightly reduced.…”

“…Various membrane fluidizers are reported to modulate HSP expression without inducing cell proteotoxicity (Balogh et al 2005;Nagy et al 2007;Balogh et al 2010). More, different disease states cause changes in the fluidity and micro-domain structure of membranes (Crul et al 2013;Török et al 2014). Based on the findings mentioned above we proposed the membrane sensor model which postulates that the membrane's physical properties and micro-domain organization play an initiating role in the HSR (Horváth et al 1998;Vigh et al 2007).…”

“…Besides, heat shock remarkably affects cellular membranes, seriously influencing its fluidity, phase state and micro-domain organization. This topic will be discussed in details (see below) (Vigh et al 1998;Vigh et al 2005;Balogh et al 2013;Török et al 2014). …”

“…On the other hand, isothermal membrane perturbations induced by membrane stressors (like chemical fluidizers), are reported to initiate the HSR (Horváth et al 2012;Balogh et al 2013;Török et al 2014;Vigh et al 1998). Detailed information will be given in section 1.6.1.1 "Membrane initiated stress signaling".…”

“…PM composed of proteins and lipids regulates cell signaling and many other cellular processes through its unique "dynamic, yet structured" feature (Vereb et al 2003;Escribá et al 2008;Kusumi et al 2012;Török et al 2014). According to the fluid mosaic model proposed by Singer and Nicolson in 1972, the PM has a two dimensional phospholipid bilayer, hosting membrane proteins which are dispersed randomly and homogenously within the lipid bilayer.…”