bims-mecosi Biomed News
on Membrane contact sites
Issue of 2023‒01‒08
seven papers selected by
Verena Kohler
  1. The Hob proteins: Putative, novel lipid transfer proteins at ER-PM contact sites.
  2. Endoplasmic reticulum protein BIK binds to and inhibits mitochondria-localized anti-apoptotic proteins.
  3. Legionella- and host-driven lipid flux at LCV-ER membrane contact sites promotes vacuole remodeling.
  4. Increased interaction between endoplasmic reticulum and mitochondria following sleep deprivation.
  5. The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria.
  6. Lonp1 and Sig-1R contribute to the counteraction of ursolic acid against ochratoxin A-induced mitochondrial apoptosis.
  7. The role of mitochondria-associated membranes mediated ROS on NLRP3 inflammasome in cardiovascular diseases.
  1. Contact (Thousand Oaks). 2021 Jan-Dec;4:4
    The Hob proteins: Putative, novel lipid transfer proteins at ER-PM contact sites.
    Sarah D Neuman, Amy T Cavanagh, Arash Bashirullah.
      Nonvesicular transfer of lipids at membrane contact sites (MCS) has recently emerged as a critical process for cellular function. Lipid transfer proteins (LTPs) mediate this unique transport mechanism, and although several LTPs are known, the cellular complement of these proteins continues to expand. Our recent work has revealed the highly conserved but poorly characterized Hobbit/Hob proteins as novel, putative LTPs at endoplasmic reticulum-plasma membrane (ER-PM) contact sites. Using both S. cerevisiae and D. melanogaster model systems, we demonstrated that the Hob proteins localize to ER-PM contact sites via an N-terminal ER membrane anchor and conserved C-terminal sequences. These conserved C-terminal sequences bind to phosphoinositides (PIPs), and the distribution of PIPs is disrupted in hobbit mutant cells. Recently released structural models of the Hob proteins exhibit remarkable similarity to other bona fide LTPs, like VPS13A and ATG2, that function at MCS. Hobbit is required for viability in Drosophila, suggesting that the Hob proteins are essential genes that may mediate lipid transfer at MCS.
    Keywords:  Drosophila; ER-PM contact sites; S. cerevisiae; lipid binding protein; lipid transfer protein; phosphoinositides
    DOI:  https://doi.org/10.1177/25152564211052376
  2. J Biol Chem. 2023 Jan 02. pii: S0021-9258(22)01306-0. [Epub ahead of print] 102863
    Endoplasmic reticulum protein BIK binds to and inhibits mitochondria-localized anti-apoptotic proteins.
    Elizabeth J Osterlund, Nehad Hirmiz, Dang Nguyen, James M Pemberton, Qiyin Fang, David W Andrews.
      The pro-apoptotic BH3-only endoplasmic reticulum (ER) resident protein BIK, positively regulates mitochondrial outer membrane permeabilization (MOMP), the point-of-no-return in apoptosis. It is generally accepted that BIK functions at a distance from mitochondria by binding and sequestering anti-apoptotic proteins at the ER thereby promoting ER calcium release. Although BIK is predominantly localized to the ER, we detect by FLIM-FRET microscopy, BH3 region-dependent direct binding between BIK and mitochondria-localized chimeric mutants of the anti-apoptotic proteins BCL-XL and BCL-2 in both BMK and MCF-7 cells. Direct binding was accompanied by cell-type specific differential relocalization in response to co-expression of either BIK or one of its target binding partners, BCL-XL, when co-expressed in cells. In BMK cells with genetic deletion of both BAX and BAK (BMK-DKO) our data suggest a fraction of BIK protein moves towards mitochondria in response to the expression of a mitochondria-localized BCL-XL mutant. In contrast, in MCF-7 cells our data suggest BIK is localized at both ER and mitochondria-associated endoplasmic reticulum membranes (MAMs) and binds to the mitochondria-localized BCL-XL mutant via relocalization of BCL-XL to ER and MAMs. Rather than functioning at a distance, our data suggest BIK initiates MOMP via direct interactions with ER and mitochondria-localized anti-apoptotic proteins, that occur via ER-mitochondria contact sites, and/or by relocalization of either BIK or anti-apoptotic proteins in cells.
    Keywords:  BCL-2 family; BCL-2 interacting killer; BIK; FLIM-FRET; apoptosis; subcellular localization fluorescence lifetime imaging microscopy
    DOI:  https://doi.org/10.1016/j.jbc.2022.102863
  3. EMBO Rep. 2023 Jan 02. e56007
    Legionella- and host-driven lipid flux at LCV-ER membrane contact sites promotes vacuole remodeling.
    Simone Vormittag, Dario Hüsler, Ina Haneburger, Tobias Kroniger, Aby Anand, Manuel Prantl, Caroline Barisch, Sandra Maaß, Dörte Becher, François Letourneur, Hubert Hilbi.
      Legionella pneumophila replicates in macrophages and amoeba within a unique compartment, the Legionella-containing vacuole (LCV). Hallmarks of LCV formation are the phosphoinositide lipid conversion from PtdIns(3)P to PtdIns(4)P, fusion with ER-derived vesicles and a tight association with the ER. Proteomics of purified LCVs indicate the presence of membrane contact sites (MCS) proteins possibly implicated in lipid exchange. Using dually fluorescence-labeled Dictyostelium discoideum amoeba, we reveal that VAMP-associated protein (Vap) and the PtdIns(4)P 4-phosphatase Sac1 localize to the ER, and Vap also localizes to the LCV membrane. Furthermore, Vap as well as Sac1 promote intracellular replication of L. pneumophila and LCV remodeling. Oxysterol binding proteins (OSBPs) preferentially localize to the ER (OSBP8) or the LCV membrane (OSBP11), respectively, and restrict (OSBP8) or promote (OSBP11) bacterial replication and LCV expansion. The sterol probes GFP-D4H* and filipin indicate that sterols are rapidly depleted from LCVs, while PtdIns(4)P accumulates. In addition to Sac1, the PtdIns(4)P-subverting L. pneumophila effector proteins LepB and SidC also support LCV remodeling. Taken together, the Legionella- and host cell-driven PtdIns(4)P gradient at LCV-ER MCSs promotes Vap-, OSBP- and Sac1-dependent pathogen vacuole maturation.
    Keywords:  Atlastin; Dictyostelium discoideum; Legionnaires' disease; Sac1 phosphoinositide phosphatase; oxysterol binding protein
    DOI:  https://doi.org/10.15252/embr.202256007
  4. BMC Biol. 2023 Jan 04. 21(1): 1
    Increased interaction between endoplasmic reticulum and mitochondria following sleep deprivation.
    Amina Aboufares El Alaoui, Edgar Buhl, Sabrina Galizia, James J L Hodge, Luisa de Vivo, Michele Bellesi.
      BACKGROUND: Prolonged cellular activity may overload cell function, leading to high rates of protein synthesis and accumulation of misfolded or unassembled proteins, which cause endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR) to re-establish normal protein homeostasis. Previous molecular work has demonstrated that sleep deprivation (SD) leads to ER stress in neurons, with a number of ER-specific proteins being upregulated to maintain optimal cellular proteostasis. It is still not clear which cellular processes activated by sleep deprivation lead to ER- stress, but increased cellular metabolism, higher request for protein synthesis, and over production of oxygen radicals have been proposed as potential contributing factors. Here, we investigate the transcriptional and ultrastructural ER and mitochondrial modifications induced by sleep loss.RESULTS: We used gene expression analysis in mouse forebrains to show that SD was associated with significant transcriptional modifications of genes involved in ER stress but also in ER-mitochondria interaction, calcium homeostasis, and mitochondrial respiratory activity. Using electron microscopy, we also showed that SD was associated with a general increase in the density of ER cisternae in pyramidal neurons of the motor cortex. Moreover, ER cisternae established new contact sites with mitochondria, the so-called mitochondria associated membranes (MAMs), important hubs for molecule shuttling, such as calcium and lipids, and for the modulation of ATP production and redox state. Finally, we demonstrated that Drosophila male mutant flies (elav > linker), in which the number of MAMs had been genetically increased, showed a reduction in the amount and consolidation of sleep without alterations in the homeostatic sleep response to SD.
    CONCLUSIONS: We provide evidence that sleep loss induces ER stress characterized by increased crosstalk between ER and mitochondria. MAMs formation associated with SD could represent a key phenomenon for the modulation of multiple cellular processes that ensure appropriate responses to increased cell metabolism. In addition, MAMs establishment may play a role in the regulation of sleep under baseline conditions.
    Keywords:  Brain; Drosophila; Electron microscopy; Mouse; Neuron; Sleep deprivation
    DOI:  https://doi.org/10.1186/s12915-022-01498-7
  5. Cell Rep. 2022 Dec 23. pii: S2211-1247(22)01798-3. [Epub ahead of print] 111899
    The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria.
    Arthur Bassot, Junsheng Chen, Kei Takahashi-Yamashiro, Megan C Yap, Christine Silvia Gibhardt, Giang N T Le, Saaya Hario, Yusuke Nasu, Jack Moore, Tomas Gutiérrez, Lucas Mina, Heather Mast, Audric Moses, Rakesh Bhat, Klaus Ballanyi, Hélène Lemieux, Roberto Sitia, Ester Zito, Ivan Bogeski, Robert E Campbell, Thomas Simmen.
      Endoplasmic reticulum (ER) homeostasis requires molecular regulators that tailor mitochondrial bioenergetics to the needs of protein folding. For instance, calnexin maintains mitochondria metabolism and mitochondria-ER contacts (MERCs) through reactive oxygen species (ROS) from NADPH oxidase 4 (NOX4). However, induction of ER stress requires a quick molecular rewiring of mitochondria to adapt to new energy needs. This machinery is not characterized. We now show that the oxidoreductase ERO1⍺ covalently interacts with protein kinase RNA-like ER kinase (PERK) upon treatment with tunicamycin. The PERK-ERO1⍺ interaction requires the C-terminal active site of ERO1⍺ and cysteine 216 of PERK. Moreover, we show that the PERK-ERO1⍺ complex promotes oxidization of MERC proteins and controls mitochondrial dynamics. Using proteinaceous probes, we determined that these functions improve ER-mitochondria Ca2+ flux to maintain bioenergetics in both organelles, while limiting oxidative stress. Therefore, the PERK-ERO1⍺ complex is a key molecular machinery that allows quick metabolic adaptation to ER stress.
    Keywords:  CP: Metabolism; CP: Molecular biology; ER; ER stress; ERO1; MAMs; MERCs; PERK; bioenergetics; endoplasmic reticulum; mitochondria; mitochondria-associated membranes; mitochondria-endoplasmic reticulum contacts; oxidoreductase
    DOI:  https://doi.org/10.1016/j.celrep.2022.111899
  6. Food Chem Toxicol. 2022 Dec 29. pii: S0278-6915(22)00790-6. [Epub ahead of print]172 113592
    Lonp1 and Sig-1R contribute to the counteraction of ursolic acid against ochratoxin A-induced mitochondrial apoptosis.
    Qipeng Zhang, Wenying Chen, Boyang Zhang, Yiwen Zhang, Yuqing Xiao, Yichen An, Lingyun Han, Huiqiong Deng, Song Yao, Hongwei Wang, Xiao Li Shen.
      Ochratoxin A (OTA), a secondary fungal metabolite with nephrotoxicity, is widespread in numerous kinds of feeds and foodstuffs. Ursolic acid (UA), a water-insoluble pentacyclic triterpene acid, exists in a wide range of food materials and medicinal plants. Our earlier researches provided preliminary evidence that mitochondria- and mitochondria-associated endoplasmic reticulum membranes (MAMs)-located stress-responsive Lon protease 1 (Lonp1) had a protective function in OTA-induced nephrotoxicity, and the renoprotective function of UA against OTA partially due to Lonp1. However, whether other MAMs-located protiens, such as endoplasmic reticulum stress (ERS)-responsive Sigma 1-type opioid receptor (Sig-1R), contribute to the protection of UA against OTA-induced nephrotoxicity together with Lonp1 needs further investigation. In this study, the cell viability, reactive oxygen species, and protein expressions of human proximal tubule epithelial-originated kidney-2 (HK-2) cells varied with OTA and/or UA/CDDO-me/AVex-73/Sig-1R siRNA treatments were determined. Results indicated that a 24 h-treatment of 5 μM OTA could significantly induce mitochondrial-mediated apoptosis via repressing Lonp1 and Sig-1R, thereby enhancing the protein expressions of GRP78, p-PERK, p-eIF2α, CHOP, IRE1α, and Bax, and inhibiting the protein expression of Bcl-2 in HK-2 cells, which could be remarkably relieved by a 2 h-pre-treatment of 4 μM UA (P < 0.05). In conclusion, through mutual promotion between Lonp1 and Sig-1R, UA could effectively relieve OTA-induced apoptosis in vitro and break the vicious cycle between oxidative stress and ERS, which activated the mitochondrial apoptosis pathway.
    Keywords:  Apoptosis; Endoplasmic reticulum stress; Mitochondria-associated ER membranes; Mycotoxin; Nephrotoxicity; Pentacyclic triterpenoid
    DOI:  https://doi.org/10.1016/j.fct.2022.113592
  7. Front Cardiovasc Med. 2022 ;9 1059576
    The role of mitochondria-associated membranes mediated ROS on NLRP3 inflammasome in cardiovascular diseases.
    Jiahao Zhao, Junli Li, Guoyong Li, Mao Chen.
      Reactive oxygen species (ROS) metabolism is essential for the homeostasis of cells. Appropriate production of ROS is an important signaling molecule, but excessive ROS production can damage cells. ROS and ROS-associated proteins can act as damage associated molecular pattern molecules (DAMPs) to activate the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in cardiovascular diseases. Previous studies have shown that there are connected sites, termed mitochondria-associated membranes (MAMs), between mitochondria and the endoplasmic reticulum. In cardiovascular disease progression, MAMs play multiple roles, the most important of which is the ability to mediate ROS generation, which further activates the NLPR3 inflammasome, exacerbating the progression of disease. In this review, the following topics will be covered: 1. Molecular structures on MAMs that can mediate ROS generation; 2. Specific mechanisms of molecule-mediated ROS generation and the molecules' roles in cardiovascular disease, 3. The effects of MAMs-mediated ROS on the NLRP3 inflammasome in cardiovascular disease. The purpose of this review is to provide a basis for subsequent clinical treatment development.
    Keywords:  NLRP3 inflammasome; atherosclerosis; mitochondria-associated membranes; myocardial hypertrophy; myocardial infarction; reactive oxygen species
    DOI:  https://doi.org/10.3389/fcvm.2022.1059576
This page is being maintained by Thomas Krichel. It was last updated on 2023‒10‒30 at 8:22.