Abstract
ER lipid raft-associated protein 1 (ERLIN1) and 2 (ERLIN2) are 40 kDa transmembrane glycoproteins belonging to the family of prohibitins, containing a PHB domain. They are generally localized in the endoplasmic reticulum (ER), where ERLIN1 forms a heteroligomeric complex with its closely related ERLIN2. Well-defined functions of ERLINS are promotion of ER-associated protein degradation, mediation of inositol 1,4,5-trisphosphate (IP3) receptors, processing and regulation of lipid metabolism. Until now, ERLINs have been exclusively considered protein markers of ER lipid raft-like microdomains. However, under pathophysiological conditions, they have been described within mitochondria-associated endoplasmic reticulum membranes (MAMs), tethering sites between ER and mitochondria, characterized by the presence of specialized raft-like subdomains enriched in cholesterol and gangliosides, which play a key role in the membrane scrambling and function. In this context, it is emerging that ER lipid raft-like microdomains proteins, i.e., ERLINs, may drive mitochondria-ER crosstalk under both physiological and pathological conditions by association with MAMs, regulating the two main processes underlined, survival and death. In this review, we describe the role of ERLINs in determining cell fate by controlling the “interchange” between apoptosis and autophagy pathways, considering that their alteration has a significant impact on the pathogenesis of several human diseases.
Highlights
Preferential interactions between lipids and proteins lead to the organization of specialized sphingolipid-based microdomains on both plasma membrane and distinct organelle membranes in different cell types.evidence which has accumulated over the last two decades strongly supports the view that interactions between specific lipids, including cholesterol and sphingomyelin, leading to the formation of functionally important and relatively liquid-ordered (Lo) domains, termed lipid rafts, which move within a fluid bilayer of cellular membranes, allowing the recruitment of other lipids and proteins [1,2]
Evidence which has accumulated over the last two decades strongly supports the view that interactions between specific lipids, including cholesterol and sphingomyelin, leading to the formation of functionally important and relatively liquid-ordered (Lo) domains, termed lipid rafts, which move within a fluid bilayer of cellular membranes, allowing the recruitment of other lipids and proteins [1,2]
Cholesterol is considered essential to ensure lipid rafts formation on nuclear membrane, where it can exist in two principal pools: as sphingomyelin-free cholesterol without variation during cell proliferation and as sphingomyelin-linked cholesterol, which can be altered during the S-phase of the cell cycle when the nuclear-sphingomyelinase is activated [49]
Summary
Preferential interactions between lipids and proteins lead to the organization of specialized sphingolipid-based microdomains on both plasma membrane and distinct organelle membranes in different cell types. Cholesterol and sphingolipids are important rafts components, gangliosides, sialic-acid containing glycosphingolipids (GSLs), are highly enriched in these regions where interact with cholesterol [3]. Consistent with these data, GSLs have been proposed as a core component of lipid rafts and are used as typical lipid raft markers [4,5,6]. It has become evident that a complex network of lipid–lipid and lipid–protein interactions contribute to the activation of a variety of signaling pathways able to influence cell homeostasis [2] In this way, lipid rafts contribute to regulate a variety of signal transduction pathways responsible for specific cellular programs, including apoptosis, proliferation, differentiation, stress responses, necrosis, inflammation, autophagy and senescence, determining cell fate [18]
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