scholarly journals Closing the Gap: Membrane Contact Sites in the Regulation of Autophagy

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1184
Author(s):  
Verena Kohler ◽  
Andreas Aufschnaiter ◽  
Sabrina Büttner
Keyword(s):  
Mammalian Cells ◽  
Functional Integration ◽  
Lipid Synthesis ◽  
Spatial Separation ◽  
Biochemical Processes ◽  
Cellular Processes ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
Related Proteins

In all eukaryotic cells, intracellular organization and spatial separation of incompatible biochemical processes is established by individual cellular subcompartments in form of membrane-bound organelles. Virtually all of these organelles are physically connected via membrane contact sites (MCS), allowing interorganellar communication and a functional integration of cellular processes. These MCS coordinate the exchange of diverse metabolites and serve as hubs for lipid synthesis and trafficking. While this of course indirectly impacts on a plethora of biological functions, including autophagy, accumulating evidence shows that MCS can also directly regulate autophagic processes. Here, we focus on the nexus between interorganellar contacts and autophagy in yeast and mammalian cells, highlighting similarities and differences. We discuss MCS connecting the ER to mitochondria or the plasma membrane, crucial for early steps of both selective and non-selective autophagy, the yeast-specific nuclear–vacuolar tethering system and its role in microautophagy, the emerging function of distinct autophagy-related proteins in organellar tethering as well as novel MCS transiently emanating from the growing phagophore and mature autophagosome.

The role of phosphatidylinositol-transfer proteins at membrane contact sites

2016 ◽  
Vol 44 (2) ◽  
pp. 419-424 ◽  
Author(s):  
Michael Selitrennik ◽  
Sima Lev
Keyword(s):  
Underlying Mechanism ◽  
Cellular Processes ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Compartments ◽  
Potential Mode ◽  
Membrane Contact ◽  
Phosphatidylinositol Transfer ◽  
Phosphatidylinositol Transfer Proteins

Phosphatidylinositol-transfer proteins (PITPs) have been initially identified as soluble factors that accelerate the monomeric exchange of either phosphatidylinositol (PI) or phosphatidylcholine (PC) between membrane bilayers in vitro. They are highly conserved in eukaryotes and have been implicated in different cellular processes, including vesicular trafficking, signal transduction, and lipid metabolism. Recent studies suggest that PITPs function at membrane contact sites (MCSs) to facilitate the transport of PI from its synthesis site at the endoplasmic reticulum (ER) to various membrane compartments. In this review, we describe the underlying mechanism of PITPs targeting to MCSs, discuss their cellular roles and potential mode of action.

Triggering of Ca2+ signals by NAADP-gated two-pore channels: a role for membrane contact sites?

2012 ◽  
Vol 40 (1) ◽  
pp. 153-157 ◽  
Author(s):  
Sandip Patel ◽  
Eugen Brailoiu
Keyword(s):  
Endoplasmic Reticulum ◽  
Nicotinic Acid ◽  
Cellular Processes ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
Acidic Organelles ◽  
Specific Membrane ◽  
Ca2 Channels

NAADP (nicotinic acid–adenine dinucleotide phosphate) is a potent Ca2+-mobilizing messenger implicated in many Ca2+-dependent cellular processes. It is highly unusual in that it appears to trigger Ca2+ release from acidic organelles such as lysosomes. These signals are often amplified by archetypal Ca2+ channels located in the endoplasmic reticulum. Recent studies have converged on the TPCs (two-pore channels) which localize to the endolysosomal system as the likely primary targets through which NAADP mediates its effects. ‘Chatter’ between TPCs and endoplasmic reticulum Ca2+ channels is disrupted when TPCs are directed away from the endolysosomal system. This suggests that intracellular Ca2+ release channels may be closely apposed, possibly at specific membrane contact sites between acidic organelles and the endoplasmic reticulum.

scholarly journals ORP5 Transfers Phosphatidylserine To Mitochondria And Regulates Mitochondrial Calcium Uptake At Endoplasmic Reticulum - Mitochondria Contact Sites

2019 ◽  
Author(s):  
Leila Rochin ◽  
Cécile Sauvanet ◽  
Eeva Jääskeläinen ◽  
Audrey Houcine ◽  
Amita Arora ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mammalian Cells ◽  
Calcium Uptake ◽  
Vesicular Transport ◽  
Mitochondrial Calcium ◽  
Mitochondrial Membranes ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
Mitochondrial Calcium Uptake

SUMMARYMitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the two mitochondrial membranes. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at sites of close organelle apposition called membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that ORP5/8 mediate non-vesicular transport of Phosphatidylserine (PS) from the ER to mitochondria in mammalian cells. We also show that ER-mitochondria contacts where ORP5/8 reside are physically and functionally linked to the MIB/MICOS complexes that bridge the mitochondrial membranes, cooperating with them to facilitate PS transfer from the ER to the mitochondria. Finally, we show that ORP5 but not ORP8, additionally regulates import of calcium to mitochondria and consequently cell senescence.

scholarly journals Di-arginine and FFAT-like motifs retain a subpopulation of PRA1 at ER-mitochondria membrane contact sites

2020 ◽  
Author(s):  
Ameair Abu Irqeba ◽  
Judith Mosinger Ogilvie
Keyword(s):  
Mammalian Cells ◽  
Protein Localization ◽  
Transmembrane Protein ◽  
Amino Acid Sequences ◽  
Terminal Region ◽  
Rab Gtpases ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Er Retention ◽  
Membrane Contact

ABSTRACTPrenylated Rab Acceptor 1 (PRA1/Rabac1) is a four-pass transmembrane protein that has been found to localize to the Golgi and promiscuously associate with a diverse array of Rab GTPases. We have previously identified PRA1 to be among the earliest significantly down-regulated genes in the rd1 mouse model of retinitis pigmentosa, a retinal degenerative disease. Here, we show that an endogenous subpopulation of PRA1 resides within the endoplasmic reticulum (ER) at ER-mitochondria membrane contact sites in cultured mammalian cells. We also demonstrate that PRA1 contains two previously unidentified ER retention/retrieval amino acid sequences on its cytosolic N-terminal region: a membrane distal di-arginine motif and a novel membrane proximal FFAT-like motif. Using a truncation construct that lacks complete Golgi targeting information, we show that mutation of either motif leads to an increase in cell surface localization, while mutation of both motifs exhibits an additive effect. We also present evidence that illustrates that N- or C- terminal addition of a tag to full-length PRA1 leads to differential localization to either the Golgi or reticular ER, phenotypes that do not completely mirror endogenous protein localization. The presence of multiple ER retention motifs on the PRA1 N-terminal region further suggests that it has a functional role within the ER.

scholarly journals OSBP-Related Protein Family in Lipid Transport over Membrane Contact Sites

2015 ◽  
Vol 8s1 ◽  
pp. LPI.S31726 ◽  
Author(s):  
Vesa M. Olkkonen
Keyword(s):  
Endoplasmic Reticulum ◽  
Mammalian Cells ◽  
Binding Protein ◽  
High Capacity ◽  
Retrograde Transport ◽  
Protein Family ◽  
Oxysterol Binding Protein ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact

Increasing evidence suggests that oxysterol-binding protein-related proteins (ORPs) localize at membrane contact sites, which are high-capacity platforms for inter-organelle exchange of small molecules and information. ORPs can simultaneously associate with the two apposed membranes and transfer lipids across the interbilayer gap. Oxysterol-binding protein moves cholesterol from the endoplasmic reticulum to trans-Golgi, driven by the retrograde transport of phosphatidylinositol-4-phosphate (PI4P). Analogously, yeast Osh6p mediates the transport of phosphatidylserine from the endoplasmic reticulum to the plasma membrane in exchange for PI4P, and ORP5 and -8 are suggested to execute similar functions in mammalian cells. ORPs may share the capacity to bind PI4P within their ligand-binding domain, prompting the hypothesis that bidirectional transport of a phosphoinositide and another lipid may be a common theme among the protein family. This model, however, needs more experimental support and does not exclude a function of ORPs in lipid signaling.

Oxysterol binding proteins: in more than one place at one time?

2004 ◽  
Vol 82 (1) ◽  
pp. 87-98 ◽  
Author(s):  
Vesa M Olkkonen ◽  
Timothy P Levine
Keyword(s):  
Cholesterol Transport ◽  
Liver X Receptors ◽  
Oxysterol Binding Protein ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Expression Of Genes ◽  
Interaction Partners ◽  
Membrane Contact ◽  
X Receptors ◽  
Related Proteins

Oxysterols are potent signalling lipids that directly bind liver X receptors (LXRs) and a subset of oxysterol binding protein (OSBP) related proteins (ORPs). It is relatively well established that the oxysterol-regulated function of LXRs is to control the expression of genes involved in reverse cholesterol transport, catabolism of cholesterol, and lipogenesis. In contrast, the mechanisms by which oxysterols and ORPs affect cellular lipid metabolism have remained poorly understood. In this review, we summarize the information available on function of the ORPs and compare the two families of proteins binding oxysterol to demonstrate the different responses that similar lipids can elicit within cells. The other focus is on the membrane targeting determinants and the protein interaction partners of ORPs, which provide interesting clues to the mode(s) of ORP action. Specifically, we suggest a model in which a general property of ORPs is to function at membrane contact sites, specialized zones of communication between two different organelles.Key words: endoplasmic reticulum, lipid transport, LXR, membrane contact sites, ORP, OSBP, Osh, sterol metabolism.

scholarly journals Lipid synthesis and membrane contact sites: a crossroads for cellular physiology

2016 ◽  
Vol 57 (10) ◽  
pp. 1789-1805 ◽  
Author(s):  
J. Pedro Fernández-Murray ◽  
Christopher R. McMaster
Keyword(s):  
Lipid Synthesis ◽  
Cellular Physiology ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact

scholarly journals Endoplasmic Reticulum–Plasma Membrane Contact Sites: Regulators, Mechanisms, and Physiological Functions

2021 ◽  
Vol 9 ◽  
Author(s):  
Chenlu Li ◽  
Tiantian Qian ◽  
Ruyue He ◽  
Chun Wan ◽  
Yinghui Liu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
Lipid Homeostasis ◽  
Ion Dynamics ◽  
Cellular Processes ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Intracellular Signals ◽  
Membrane Contact ◽  
External Stimuli

The endoplasmic reticulum (ER) forms direct membrane contact sites with the plasma membrane (PM) in eukaryotic cells. These ER-PM contact sites play essential roles in lipid homeostasis, ion dynamics, and cell signaling, which are carried out by protein-protein or protein-lipid interactions. Distinct tethering factors dynamically control the architecture of ER-PM junctions in response to intracellular signals or external stimuli. The physiological roles of ER-PM contact sites are dependent on a variety of regulators that individually or cooperatively perform functions in diverse cellular processes. This review focuses on proteins functioning at ER-PM contact sites and highlights the recent progress in their mechanisms and physiological roles.

scholarly journals The Unfolded Protein Response and Membrane Contact Sites: Tethering as a Matter of Life and Death?

Contact ◽  
2018 ◽  
Vol 1 ◽  
pp. 251525641877051 ◽  
Author(s):  
Alexander R. van Vliet ◽  
Maria Livia Sassano ◽  
Patrizia Agostinis
Keyword(s):  
Unfolded Protein Response ◽  
Cell Fate ◽  
Mammalian Cells ◽  
Cell Fate Decisions ◽  
Unfolded Protein ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
The Unfolded Protein Response ◽  
Protein Response

The endoplasmic reticulum (ER) is the most extensive organelle of the eukaryotic cell and constitutes the major site of protein and lipid synthesis and regulation of intracellular Ca2+ levels. To exert these functions properly, the ER network is shaped in structurally and functionally distinct domains that dynamically remodel in response to intrinsic and extrinsic cues. Moreover, the ER establishes a tight communication with virtually all organelles of the cell through specific subdomains called membrane contact sites. These contact sites allow preferential, nonvesicular channeling of key biological mediators including lipids and Ca2+ between organelles and are harnessed by the ER to interface with and coregulate a variety of organellar functions that are vital to maintain homeostasis. When ER homeostasis is lost, a condition that triggers the activation of an evolutionarily conserved pathway called the unfolded protein response (UPR), the ER undergoes rapid remodeling. These dynamic changes in ER morphology are functionally coupled to the modulation or formation of contact sites with key organelles, such as mitochondria and the plasma membrane, which critically regulate cell fate decisions of the ER-stressed cells. Certain components of the UPR have been shown to facilitate the formation of contact sites through various mechanisms including remodeling of the actin cytoskeleton. In this review, we discuss old and emerging evidence linking the UPR machinery to contact site formation in mammalian cells and discuss their important role in cellular homeostasis.

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