ER-PM Contact Sites – SNARING Actors in Emerging Functions

Abstract

The compartmentalisation achieved by confining cytoplasm into membrane-enclosed organelles in eukaryotic cells is essential for maintaining vital functions including ATP production, synthetic and degradative pathways. While intracellular organelles are highly specialised in these functions, the restricting membranes also impede exchange of molecules responsible for the synchronised and responsive cellular activities. The initial identification of contact sites between the ER and plasma membrane (PM) provided a potential candidate structure for communication between organelles without mixing by fusion. Over the past decades, research has revealed a far broader picture of the events. Membrane contact sites (MCSs) have been recognized as increasingly important actors in cell differentiation, plasticity and maintenance, and, upon dysfunction, responsible for pathological conditions such as cancer and neurodegenerative diseases. Present in multiple organelles and cell types, MCSs promote transport of lipids and Ca2+ homoeostasis, with a range of associated protein families. Interestingly, each MCS displays a unique molecular signature, adapted to organelle functions. This review will explore the literature describing the molecular components and interactions taking place at ER-PM contact sites, their functions, and implications in eukaryotic cells, particularly neurons, with emphasis on lipid transfer proteins and emerging function of SNAREs.

Controlling contacts—Molecular mechanisms to regulate organelle membrane tethering

“…[1][2][3] Membrane contact sites (MCS) between organelles are mediated by tether proteins and have now been described for most, if not all, organelles including mitochondria, the endoplasmic reticulum (ER), Golgi complex, endosomes, lysosomes, peroxisomes, lipid droplets and the plasma membrane. [4][5][6][7][8][9][10] Tether proteins are usually membrane proteins, which can bridge two organelles through binding another tether protein or directly to membrane lipids on the opposing membrane (Figure 1). Besides the molecular tethers, other proteins associated with MCS are involved in the transfer of small molecules (e.g., ions and lipids), as well as regulatory components.…”

The relevance of organelle interactions in cellular senescence

“…The stability of MCS requires tethering proteins, such as vesicle-associated membrane protein-associated proteins (VAPs), which play a key role in maintaining ER stability 6 , 8 , 37 . VAPs are highly conserved type II integral ER membrane proteins that can bind various intracellular proteins containing phenylalanine-phenylalanine acidic tract (FFAT) motifs 6 , 38 , 39 .…”

“…For example, ORP5 and ORP8 in the ER tether the ER to the PM through interactions with phosphatidylinositol 4-phosphate (PI(4)P) in the PM, thereby forming ER-PM MCSs to deliver PI(4)P to the ER for degradation and to deliver phosphatidylserine (PS) from the ER to the PM, to control PI(4)P levels and enrich PS in PM 8 , 48 , 49 . The E-Syts SMP domain can dimerize to form a long hydrophobic tunnel, allowing phospholipids to move between the ER and PM membranes 8 , 37 . TMEM24 promotes ER-PM MCS formation to transfer phosphatidylinositol (PI) from the ER to the PM while decreasing Ca 2+ concentration in the cytoplasm 8 .…”

“…TMEM24 promotes ER-PM MCS formation to transfer phosphatidylinositol (PI) from the ER to the PM while decreasing Ca 2+ concentration in the cytoplasm 8 . Nir2 in PM can bind to VAPs in the ER to form MCS, thus delivering PI from the ER to the PM and palmitic acid from the PM to the ER 8 , 37 , 50 .…”

Annexins Bridging the Gap: Novel Roles in Membrane Contact Site Formation

“…In addition, as outlined in more detail below, several annexins are also found in MCS. It would go beyond the scope of this Mini Review to list all proteins and we recommend excellent articles and reviews on this topic ( Alpy and Tomasetto, 2005 ; Eisenberg-Bord et al, 2016 ; Kentala et al, 2016 ; Atakpa et al, 2018 ; Hoyer et al, 2018 ; Kumar et al, 2018 ; Quon et al, 2018 ; Sandhu et al, 2018 ; Balla et al, 2019 ; Bohnert, 2019 ; Liao et al, 2019 ; Patel, 2019 ; Cremer et al, 2020 ; Islinger et al, 2020 ; Meneses-Salas et al, 2020b ; Peng et al, 2020 ; Hewlett et al, 2021 ; Reinisch and Prinz, 2021 ; Saric et al, 2021 ; Wu and Voeltz, 2021 ).…”