BBA - Molecular Cell Research (v.1864, #9)

Membrane contact sites by Benoît Kornmann; Christian Ungermann (1435-1438).

Tubular lipid binding proteins (TULIPs) growing everywhere by Louise H. Wong; Tim P. Levine (1439-1449).
Tubular lipid binding proteins (TULIPs) have become a focus of interest in the cell biology of lipid signalling, lipid traffic and membrane contact sites. Each tubular domain has an internal pocket with a hydrophobic lining that can bind a hydrophobic molecule such as a lipid. This allows TULIP proteins to carry lipids through the aqueous phase. TULIP domains were first found in a large family of extracellular proteins related to the bacterial permeability-inducing protein (BPI) and cholesterol ester transfer protein (CETP). Since then, the same fold and lipid transfer capacity have been found in SMP domains (so-called for their occurrence in synaptotagmin, mitochondrial and lipid binding proteins), which localise to intracellular membrane contact sites. Here the methods for identifying known TULIPs are described, and used to find previously unreported TULIPs, one in the silk polymer and another in prokaryotes illustrated by the E. coli protein YceB. The bacterial TULIP alters views on the likely evolution of the domain, suggesting its presence in the last universal common ancestor. The major function of TULIPs is to handle lipids, but we still do not know how they work in detail, or how many more remain to be discovered. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann.
Keywords: Anacetrapib; Cystic fibrosis transmembrane conductance regulator (CFTR); Endoplasmic reticulum-mitochondria encounter structure (ERMES); Extended-synaptotagmin (E-Syt); Lipid traffic; Lipopolysaccharide (LPS); PDZK8; Tether;

Membrane contact sites, ancient and central hubs of cellular lipid logistics by Amrita Jain; Joost C.M. Holthuis (1450-1458).
Membrane contact sites (MCSs) are regions where two organelles are closely apposed to facilitate molecular communication and promote a functional integration of compartmentalized cellular processes. There is growing evidence that MCSs play key roles in controlling intracellular lipid flows and distributions. Strikingly, even organelles connected by vesicular trafficking exchange lipids en bulk via lipid transfer proteins that operate at MCSs. Herein, we describe how MCSs developed into central hubs of lipid logistics during the evolution of eukaryotic cells. We then focus on how modern eukaryotes exploit MCSs to help solve a major logistical problem, namely to preserve the unique lipid mixtures of their early and late secretory organelles in the face of extensive vesicular trafficking. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann.
Keywords: Evolution; Golgi complex; Lipid transfer protein; Mitochondria; Secretory pathway; Sphingolipid biosynthesis;

Function of lipid droplet-organelle interactions in lipid homeostasis by Antonio Daniel Barbosa; Symeon Siniossoglou (1459-1468).
Storage of non-polar lipids in ubiquitous eukaryotic organelles, lipid droplets (LDs), prevents the toxic consequences of unesterified fatty acids and provides a lipid reservoir that can be promptly used to satisfy cellular needs under multiple metabolic and physiological conditions. Tight temporal and spatial control of LD biogenesis and mobilization of neutral lipids is essential for the correct channelling of lipid intermediates to their various cellular destinations and the maintenance of cellular homeostasis. These functions are mediated by multiple interactions between LDs and other intracellular organelles that are required for the delivery of stored lipids. Here we review recent advances in the interactions of LDs with the endoplasmic reticulum (ER), mitochondria and vacuole/lysosome. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann.
Keywords: Lipid droplet; Endoplasmic reticulum membrane; Contact site; Triacylglycerol; Vacuole; Yeast;

Mitochatting – If only we could be a fly on the cell wall by Michal Eisenberg-Bord; Maya Schuldiner (1469-1480).
Mitochondria, cellular metabolic hubs, perform many essential processes and are required for the production of metabolites such as ATP, iron-sulfur clusters, heme, amino acids and nucleotides. To fulfill their multiple roles, mitochondria must communicate with all other organelles to exchange small molecules, ions and lipids. Since mitochondria are largely excluded from vesicular trafficking routes, they heavily rely on membrane contact sites. Contact sites are areas of close proximity between organelles that allow efficient transfer of molecules, saving the need for slow and untargeted diffusion through the cytosol. More globally, multiple metabolic pathways require coordination between mitochondria and additional organelles and mitochondrial activity affects all other cellular entities and vice versa. Therefore, uncovering the different means of mitochondrial communication will allow us a better understanding of mitochondria and may illuminate disease processes that occur in the absence of proper cross-talk. In this review we focus on how mitochondria interact with all other organelles and emphasize how this communication is essential for mitochondrial and cellular homeostasis. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann.
Keywords: Mitochondria; Contact sites; Lipid transfer; Peroxisomes; Lipid droplets; Endoplasmic reticulum;

Mitochondrial contact site and cristae organizing system: A central player in membrane shaping and crosstalk by Florian Wollweber; Karina von der Malsburg; Martin van der Laan (1481-1489).
Mitochondria are multifunctional metabolic factories and integrative signaling organelles of eukaryotic cells. The structural basis for their numerous functions is a complex and dynamic double-membrane architecture. The outer membrane connects mitochondria to the cytosol and other organelles. The inner membrane is composed of a boundary region and highly folded cristae membranes. The evolutionarily conserved mitochondrial contact site and cristae organizing system (MICOS) connects the two inner membrane domains via formation and stabilization of crista junction structures. Moreover, MICOS establishes contact sites between inner and outer mitochondrial membranes by interacting with outer membrane protein complexes. MICOS deficiency leads to a grossly altered inner membrane architecture resulting in far-reaching functional perturbations in mitochondria. Consequently, mutations affecting the function of MICOS are responsible for a diverse spectrum of human diseases. In this article, we summarize recent insights and concepts on the role of MICOS in the organization of mitochondrial membranes. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann.
Keywords: Mitochondria; Cristae; Membrane organization; Contact sites; MICOS;

The Extended-Synaptotagmins by Yasunori Saheki; Pietro De Camilli (1490-1493).
The extended-synaptotagmins (tricalbins in yeast) derive their name from their partial domain structure similarity to the synaptotagmins, which are characterized by an N-terminal membrane anchor and cytosolically exposed C2 domains. However, they differ from the synaptotagmins in localization and function. The synaptotagmins tether secretory vesicles, including synaptic vesicles, to the plasma membrane (PM) via their C2 domains and regulate their Ca2 + triggered exocytosis. In contrast, the extended-synaptotagmins are resident proteins of the endoplasmic reticulum (ER), which tether this organelle to the plasma membrane via their C2 domains, but not as a premise to fusion of the two membranes. They transport glycerolipids between the two bilayers via their lipid-harboring SMP domains and Ca2 + regulates their membrane tethering and lipid transport function. Additionally, the extended-synaptotagmins are more widely expressed in different organisms, as they are present not only in animal cells, but also in fungi and plants, which do not express the synaptotagmins. Thus, they have a more general function than the synaptotagmins, whose appearance in animal species correlated with the occurrence of Ca2 + triggered exocytosis. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann.
Keywords: Synaptotagmin; Tricalbin; TULIP; SMP; C2;

ER-plasma membrane junctions: Why and how do we study them? by Chi-Lun Chang; Yu-Ju Chen; Jen Liou (1494-1506).
Endoplasmic reticulum (ER)-plasma membrane (PM) junctions are membrane microdomains important for communication between the ER and the PM. ER-PM junctions were first reported in muscle cells in 1957, but mostly ignored in non-excitable cells due to their scarcity and lack of functional significance. In 2005, the discovery of stromal interaction molecule 1 (STIM1) mediating a universal Ca2+ feedback mechanism at ER-PM junctions in mammalian cells led to a resurgence of research interests toward ER-PM junctions. In the past decade, several major advancements have been made in this emerging topic in cell biology, including the generation of tools for labeling ER-PM junctions and the unraveling of mechanisms underlying regulation and functions of ER-PM junctions. This review summarizes early studies, recently developed tools, and current advances in the characterization and understanding of ER-PM junctions. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann.

Deciphering the molecular architecture of membrane contact sites by cryo-electron tomography by Javier Collado; Rubén Fernández-Busnadiego (1507-1512).
At membrane contact sites (MCS) two cellular membranes form tight appositions that play critical roles in fundamental phenomena such as lipid metabolism or Ca2 + homeostasis. The interest for these structures has surged in recent years, bringing about the characterization of a plethora of MCS-resident molecules. How those molecules are structurally organized at MCS remains enigmatic, limiting our understanding of MCS function. Whereas such molecular detail is obscured by conventional electron microscopy sample preparation, cryo-electron tomography (cryo-ET) allows high resolution imaging of cellular landscapes in close-to-native conditions. Here we briefly review the fundamentals of cryo-ET and how recent developments in this technique are beginning to unveil the molecular architecture of MCS. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann.
Keywords: Cryo-EM; Cryo-focused ion beam milling; Vitrification; Endoplasmic reticulum; Extended synaptotagmin; Membrane tether;

The ER phagosome connection in the era of membrane contact sites by Paula Nunes-Hasler; Nicolas Demaurex (1513-1524).
Phagocytosis is an essential mechanism through which innate immune cells ingest foreign material that is either destroyed or used to generate and present antigens and initiate adaptive immune responses. While a role for the ER during phagosome biogenesis has been recognized, whether fusion with ER cisternae or vesicular derivatives occurs has been the source of much contention. Membrane contact sites (MCS) are tight appositions between ER membranes and various organelles that coordinate multiple functions including localized signalling, lipid transfer and trafficking. The discovery that MCS form between the ER and phagosomes now begs the question of whether MCS play a role in connecting the ER to phagosomes under different contexts. In this review, we consider the implications of MCS between the ER and phagosomes during cross-presentation and infection with intracellular pathogens. We also discuss the similarities between these contacts and those between the ER and plasma membrane and acidic organelles such as endosomes and lysosomes. This article is part of a Special Issue entitled: Membrane Contact Sites edited by Christian Ungermann and Benoit Kornmann.
Keywords: Phagocytosis; Endoplasmic reticulum; Junctional ER; Cortical ER; Legionella pneumophila; Toxoplasma gondii;