bims-mecosi Biomed News
on Membrane contact sites
Issue of 2023–07–23
eleven papers selected by
Verena Kohler, University of Graz
  1. The Organization and Function of the Phagophore-ER Membrane Contact Sites.
  2. Oxysterol-Binding Protein: new insights into lipid transport functions and human diseases.
  3. Stranger Twins: A Tale of Resemblance and Contrast Between VAP Proteins.
  4. Bridge-Like Lipid Transfer Proteins (BLTPs) in C. elegans: From Genetics to Structures and Functions.
  5. Regulation of store-operated Ca2+ entry by IP3 receptors independent of their ability to release Ca2.
  6. Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson's disease.
  7. Protrudin-mediated ER-endosome contact sites promote phagocytosis.
  8. Endoplasmic reticulum stress and mitochondrial dysfunction during aging: Role of sphingolipids.
  9. Bacterial AsmA-Like Proteins: Bridging the Gap in Intermembrane Phospholipid Transport.
  10. Phosphoinositides in New Spaces.
  11. Mitochondrial-Derived Compartments are Multilamellar Domains that Encase Membrane Cargo and Cytosol.
  1. Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564231183898
    The Organization and Function of the Phagophore-ER Membrane Contact Sites.
    Prado Vargas Duarte, Fulvio Reggiori.
      Macroautophagy is characterized by the de novo formation of double-membrane vesicles termed autophagosomes. The precursor structure of autophagosomes is a membrane cistern called phagophore, which elongates through a massive acquisition of lipids until closure. The phagophore establishes membrane-contact sites (MCSs) with the endoplasmic reticulum (ER), where conserved ATG proteins belonging to the ATG9 lipid scramblase, ATG2 lipid transfer and Atg18/WIPI4 β-propeller families concentrate. Several recent in vivo and in vitro studies have uncovered the relevance of these proteins and MCSs in the lipid supply required for autophagosome formation. Although important conceptual advances have been reached, the functional interrelationship between ATG9, ATG2 and Atg18/WIPI4 proteins at the phagophore-ER MCSs and their role in the phagophore expansion are not completely understood. In this review, we describe the current knowledge about the structure, interactions, localizations, and molecular functions of these proteins, with a particular emphasis on the yeast Saccharomyces cerevisiae and mammalian systems.
    Keywords:  ATG protein; ATG2; ATG9; Atg18/WIPI4; autophagosome; autophagy; lipid transfer; phagophore; scramblase; tethering
    DOI:  https://doi.org/10.1177/25152564231183898
  2. Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Jul 16. pii: S1388-1981(23)00089-6. [Epub ahead of print]1868(9): 159365
    Oxysterol-Binding Protein: new insights into lipid transport functions and human diseases.
    Yani Lin, Liyuan Ran, Ximing Du, Hongyuan Yang, Yingjie Wu.
      Oxysterol-binding protein (OSBP) mediates lipid exchange between organelles at membrane contact sites, thereby regulating lipid dynamics and homeostasis. How OSBP's lipid transfer function impacts health and disease remain to be elucidated. In this review, we first summarize the structural characteristics and lipid transport functions of OSBP, and then focus on recent progresses linking OSBP with fatty liver disease, diabetes, lysosome-related diseases, cancer and viral infections, with the aim of discovering novel therapeutic strategies for common human diseases.
    Keywords:  Cholesterol; Disease; OSBP; PI4P; Virus
    DOI:  https://doi.org/10.1016/j.bbalip.2023.159365
  3. Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564231183897
    Stranger Twins: A Tale of Resemblance and Contrast Between VAP Proteins.
    Mélody Subra, Zoé Grimanelli, Romain Gautier, Bruno Mesmin.
      When considering the vesicle-associated membrane protein-associated protein (VAP) family, major receptors at the surface of the endoplasmic reticulum (ER), it appears that VAP-A and VAP-B paralogs largely overlap in structure and function, and that specific features to distinguish these two proteins hardly exist or are poorly documented. Here, we question the degree of redundancy between VAP-A and VAP-B: is one simply a backup plan, in case of loss of function of one of the two genes, or are there molecular and functional divergences that would explain their maintenance during evolution?
    Keywords:  VAP; endoplasmic reticulum; membrane contact sites; structural biology; tether
    DOI:  https://doi.org/10.1177/25152564231183897
  4. Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564231186489
    Bridge-Like Lipid Transfer Proteins (BLTPs) in C. elegans: From Genetics to Structures and Functions.
    Taruna Pandey, Jianxiu Zhang, Bingying Wang, Dengke K Ma.
      In eukaryotic cells, lipid transfer can occur at membrane contact sites (MCS) to facilitate the exchange of various lipids between two adjacent cellular organelle membranes. Lipid transfer proteins (LTPs), including shuttle LTP or bridge-like LTP (BLTP), transport lipids at MCS and are critical for diverse cellular processes, including lipid metabolism, membrane trafficking, and cell signaling. BLTPs (BLTP1-5, including the ATG2 and VPS13 family proteins) contain lipid-accommodating hydrophobic repeating β-groove (RBG) domains that allow the bulk transfer of lipids through MCS. Compared with vesicular lipid transfer and shuttle LTP, BLTPs have been only recently identified. Their functions and regulatory mechanisms are currently being unraveled in various model organisms and by diverse approaches. In this review, we summarize the genetics, structural features, and biological functions of BLTP in the genetically tractable model organism C. elegans. We discuss our recent studies and findings on C. elegans LPD-3, a prototypical megaprotein ortholog of BLTP1, with identified lipid transfer functions that are evolutionarily conserved in multicellular organisms and in human cells. We also highlight areas for future research of BLTP using C. elegans and complementary model systems and approaches. Given the emerging links of BLTP to several human diseases, including Parkinson's disease and Alkuraya-Kučinskas syndrome, discovering evolutionarily conserved roles of BLTPs and their mechanisms of regulation and action should contribute to new advances in basic cell biology and potential therapeutic development for related human disorders.
    Keywords:  Alkuraya-Kučinskas syndrome; C. elegans; bridge-like lipid transfer (BLTP); membrane contact site (MCS); non-vesicular lipid transport; phospholipid; thermal stress
    DOI:  https://doi.org/10.1177/25152564231186489
  5. Elife. 2023 Jul 19. pii: e80447. [Epub ahead of print]12
    Regulation of store-operated Ca2+ entry by IP3 receptors independent of their ability to release Ca2.
    Pragnya Chakraborty, Bipan Kumar Deb, Vikas Arige, Thasneem Musthafa, Sundeep Malik, David I Yule, Colin W Taylor, Gaiti Hasan.
      Loss of endoplasmic reticular (ER) Ca2+ activates store-operated Ca2+ entry (SOCE) by causing the ER localized Ca2+ sensor STIM to unfurl domains that activate Orai channels in the plasma membrane at membrane contact sites (MCS). Here we demonstrate a novel mechanism by which the inositol 1,4,5 trisphosphate receptor (IP3R), an ER-localized IP3-gated Ca2+ channel, regulates neuronal SOCE. In human neurons, SOCE evoked by pharmacological depletion of ER-Ca2+ is attenuated by loss of IP3Rs, and restored by expression of IP3Rs even when they cannot release Ca2+, but only if the IP3Rs can bind IP3. Imaging studies demonstrate that IP3Rs enhance association of STIM1 with Orai1 in neuronal cells with empty stores; this requires an IP3-binding site, but not a pore. Convergent regulation by IP3Rs, may tune neuronal SOCE to respond selectively to receptors that generate IP3.
    Keywords:  cell biology; human; neuroscience
    DOI:  https://doi.org/10.7554/eLife.80447
  6. Sci Adv. 2023 Jul 21. 9(29): eadh3347
    Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson's disease.
    Wesley Peng, Leonie F Schröder, Pingping Song, Yvette C Wong, Dimitri Krainc.
      Mutations in the E3 ubiquitin ligase parkin are the most common cause of early-onset Parkinson's disease (PD). Although parkin modulates mitochondrial and endolysosomal homeostasis during cellular stress, whether parkin regulates mitochondrial and lysosomal cross-talk under physiologic conditions remains unresolved. Using transcriptomics, metabolomics and super-resolution microscopy, we identify amino acid metabolism as a disrupted pathway in iPSC-derived dopaminergic neurons from patients with parkin PD. Compared to isogenic controls, parkin mutant neurons exhibit decreased mitochondria-lysosome contacts via destabilization of active Rab7. Subcellular metabolomics in parkin mutant neurons reveals amino acid accumulation in lysosomes and their deficiency in mitochondria. Knockdown of the Rab7 GTPase-activating protein TBC1D15 restores mitochondria-lysosome tethering and ameliorates cellular and subcellular amino acid profiles in parkin mutant neurons. Our data thus uncover a function of parkin in promoting mitochondrial and lysosomal amino acid homeostasis through stabilization of mitochondria-lysosome contacts and suggest that modulation of interorganelle contacts may serve as a potential target for ameliorating amino acid dyshomeostasis in disease.
    DOI:  https://doi.org/10.1126/sciadv.adh3347
  7. Cell Mol Life Sci. 2023 Jul 19. 80(8): 216
    Protrudin-mediated ER-endosome contact sites promote phagocytosis.
    Liv Anker Elfmark, Eva Maria Wenzel, Ling Wang, Nina Marie Pedersen, Harald Stenmark, Camilla Raiborg.
      During phagocytosis, endosomes both contribute with membrane to forming phagosomes and promote phagosome maturation. However, how these vesicles are delivered to the phagocytic cup and the phagosome has been unknown. Here, we show that Protrudin-mediated endoplasmic reticulum (ER)-endosome contact sites facilitate anterograde translocation of FYCO1 and VAMP7-positive late endosomes and lysosomes (LELys) to forming phagocytic cups in a retinal pigment epithelial-derived cell line (RPE1). Protrudin-dependent phagocytic cup formation required SYT7, which promotes fusion of LELys with the plasma membrane. RPE1 cells perform phagocytosis of dead cells (efferocytosis) that expose phosphatidylserine (PS) on their surface. Exogenous addition of apoptotic bodies increased the formation of phagocytic cups, which further increased when Protrudin was overexpressed. Overexpression of Protrudin also led to elevated uptake of silica beads coated with PS. Conversely, Protrudin depletion or abrogation of ER-endosome contact sites inhibited phagocytic cup formation resulting in reduced uptake of PS-coated beads. Thus, the Protrudin pathway delivers endosomes to facilitate formation of the phagocytic cup important for PS-dependent phagocytosis.
    Keywords:  Efferocytosis; Endosomes; FYCO1; Phagocytosis; Protrudin; RAB7; VAMP7
    DOI:  https://doi.org/10.1007/s00018-023-04862-0
  8. Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Jul 18. pii: S1388-1981(23)00090-2. [Epub ahead of print] 159366
    Endoplasmic reticulum stress and mitochondrial dysfunction during aging: Role of sphingolipids.
    Qun Chen, Anna Kovilakath, Jeremy Allegood, Jeremy Thompson, Ying Hu, L Ashley Cowart, Edward J Lesnefsky.
      The endoplasmic reticulum (ER) plays a key role in the regulation of protein folding, lipid synthesis, calcium homeostasis, and serves as a primary site of sphingolipid biosynthesis. ER stress (ER dysfunction) participates in the development of mitochondrial dysfunction during aging. Mitochondria are in close contact with the ER through shared mitochondria associated membranes (MAM). Alteration of sphingolipids contributes to mitochondria-driven cell injury. Cardiolipin is a phospholipid that is critical to maintain enzyme activity in the electron transport chain. The aim of the current study was to characterize the changes in sphingolipids and cardiolipin in ER, MAM, and mitochondria during the progression of aging in young (3 mo.), middle (18 mo.), and aged (24 mo.) C57Bl/6 mouse hearts. ER stress increased in hearts from 18 mo. mice and mice exhibited mitochondrial dysfunction by 24 mo. Hearts were pooled to isolate ER, MAM, and subsarcolemmal mitochondria (SSM). LC-MS/MS quantification of lipid content showed that aging increased ceramide content in ER and MAM. In addition, the contents of sphingomyelin and monohexosylceramides are also increased in the ER from aged mice. Aging increased the total cardiolipin content in the ER. Aging did not alter the total cardiolipin content in mitochondria or MAM yet altered the composition of cardiolipin with aging in line with increased oxidative stress compared to young mice. These results indicate that alteration of sphingolipids can contribute to the ER stress and mitochondrial dysfunction that occurs during aging.
    Keywords:  Aging; Ceramide; Monohexosylceramides; Sphingomyelin; electron transport chain
    DOI:  https://doi.org/10.1016/j.bbalip.2023.159366
  9. Contact (Thousand Oaks). 2023 Jan-Dec;6:6 25152564231185931
    Bacterial AsmA-Like Proteins: Bridging the Gap in Intermembrane Phospholipid Transport.
    Sujeet Kumar, Natividad Ruiz.
      In eukaryotic cells, nonvesicular lipid transport between organelles is mediated by lipid-transfer proteins. Recently, a new class of these lipid transporters has been described to facilitate the bulk of inter-organelle lipid transport at contact sites by forming bridge-like structures with a hydrophobic groove through which lipids travel. Because their predicted structure is composed of repeating β-groove (RBG) domains, they have been named the RBG protein superfamily. Early studies on RBG proteins VPS13 and ATG2 recognized the resemblance of their predicted structures to that of the bacterial Lpt system, which transports newly synthesized lipopolysaccharides (LPS) between the inner and the outer membranes (IMs and OMs) of Gram-negative bacteria. In these didermic bacteria, the IMs and OMs are separated by an aqueous periplasmic compartment that is traversed by a bridge-like structure built with β-jelly roll domains from several Lpt proteins that provides a hydrophobic groove for LPS molecules to travel across the periplasm. Despite structural and functional similarities between RBG proteins and the Lpt system, the bacterial AsmA-like protein family has recently emerged as the likely ancestor of RBG proteins and long sought-after transporters that facilitate the transfer of phospholipids from the IM to the OM. Here, we review our current understanding of the structure and function of bacterial AsmA-like proteins, mainly focusing on recent studies that have led to the proposal that AsmA-like proteins mediate the bulk of phospholipid transfer between the IMs and OMs.
    Keywords:  LPS; glycerophospholipid; membrane biogenesis; tamB; ydbH; yhdP
    DOI:  https://doi.org/10.1177/25152564231185931
  10. Cold Spring Harb Perspect Biol. 2023 Jul 18. pii: a041406. [Epub ahead of print]
    Phosphoinositides in New Spaces.
    Elizabeth Michele Davies, Christina Anne Mitchell, Harald Alfred Stenmark.
      Phosphoinositides (PIs) are phospholipids derived from phosphatidylinositol. PIs are regulated via reversible phosphorylation, which is directed by the opposing actions of PI kinases and phosphatases. PIs constitute a minor fraction of the total cellular lipid pool but play pleiotropic roles in multiple aspects of cell biology. Genetic mutations of PI regulatory enzymes have been identified in rare congenital developmental syndromes, including ciliopathies, and in numerous human diseases, such as cancer and metabolic and neurological disorders. Accordingly, PI regulatory enzymes have been targeted in the design of potential therapeutic interventions for human diseases. Recent advances place PIs as central regulators of membrane dynamics within functionally distinct subcellular compartments. This brief review focuses on the emerging role PIs play in regulating cell signaling within the primary cilium and in directing transfer of molecules at interorganelle membrane contact sites and identifies new roles for PIs in subcellular spaces.
    DOI:  https://doi.org/10.1101/cshperspect.a041406
  11. bioRxiv. 2023 Jul 07. pii: 2023.07.07.548169. [Epub ahead of print]
    Mitochondrial-Derived Compartments are Multilamellar Domains that Encase Membrane Cargo and Cytosol.
    Zachary N Wilson, Matt West, Alyssa M English, Greg Odorizzi, Adam L Hughes.
      Preserving the health of the mitochondrial network is critical to cell viability and longevity. To do so, mitochondria employ several membrane remodeling mechanisms, including the formation of mitochondrial-derived vesicles (MDVs) and compartments (MDCs) to selectively remove portions of the organelle. In contrast to well-characterized MDVs, the distinguishing features of MDC formation and composition remain unclear. Here we used electron tomography to observe that MDCs form as large, multilamellar domains that generate concentric spherical compartments emerging from mitochondrial tubules at ER-mitochondria contact sites. Time-lapse fluorescence microscopy of MDC biogenesis revealed that mitochondrial membrane extensions repeatedly elongate, coalesce, and invaginate to form these compartments that encase multiple layers of membrane. As such, MDCs strongly sequester portions of the outer mitochondrial membrane, securing membrane cargo into a protected domain, while also enclosing cytosolic material within the MDC lumen. Collectively, our results provide a model for MDC formation and describe key features that distinguish MDCs from other previously identified mitochondrial structures and cargo-sorting domains.
    SUMMARY: Wilson and colleagues use electron tomography and time-lapse fluorescence microscopy to observe that mitochondrial-derived compartments (MDCs) are generated from outer mitochondrial membrane extensions that repeatedly elongate, coalesce, and invaginate to secure membrane cargo and cytosol within a distinct, protected domain.
    DOI:  https://doi.org/10.1101/2023.07.07.548169
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