bims-mecosi 2021-12-19 papers

Issue of 2021–12–19
four papers selected by
Verena Kohler, Stockholm University

Front Cell Dev Biol. 2021 ;9 784367

Mechanisms of Non-Vesicular Exchange of Lipids at Membrane Contact Sites: Of Shuttles, Tunnels and, Funnels.

Eukaryotic cells are characterized by their exquisite compartmentalization resulting from a cornucopia of membrane-bound organelles. Each of these compartments hosts a flurry of biochemical reactions and supports biological functions such as genome storage, membrane protein and lipid biosynthesis/degradation and ATP synthesis, all essential to cellular life. Acting as hubs for the transfer of matter and signals between organelles and throughout the cell, membrane contacts sites (MCSs), sites of close apposition between membranes from different organelles, are essential to cellular homeostasis. One of the now well-acknowledged function of MCSs involves the non-vesicular trafficking of lipids; its characterization answered one long-standing question of eukaryotic cell biology revealing how some organelles receive and distribute their membrane lipids in absence of vesicular trafficking. The endoplasmic reticulum (ER) in synergy with the mitochondria, stands as the nexus for the biosynthesis and distribution of phospholipids (PLs) throughout the cell by contacting nearly all other organelle types. MCSs create and maintain lipid fluxes and gradients essential to the functional asymmetry and polarity of biological membranes throughout the cell. Membrane apposition is mediated by proteinaceous tethers some of which function as lipid transfer proteins (LTPs). We summarize here the current state of mechanistic knowledge of some of the major classes of LTPs and tethers based on the available atomic to near-atomic resolution structures of several "model" MCSs from yeast but also in Metazoans; we describe different models of lipid transfer at MCSs and analyze the determinants of their specificity and directionality. Each of these systems illustrate fundamental principles and mechanisms for the non-vesicular exchange of lipids between eukaryotic membrane-bound organelles essential to a wide range of cellular processes such as at PL biosynthesis and distribution, lipid storage, autophagy and organelle biogenesis.

Keywords: autophagy; lipid distribution; lipid transfer protein; lipid-droplet; membrane asymmetry; membrane contact site; mitochondria-attached membranes; organelle

DOI: https://doi.org/10.3389/fcell.2021.784367

Proc Jpn Acad Ser B Phys Biol Sci. 2021 ;97(10): 559-572

New insights into the regulation of synaptic transmission and plasticity by the endoplasmic reticulum and its membrane contacts.

Masafumi Tsuboi, Yusuke Hirabayashi.

Mammalian neurons are highly compartmentalized yet very large cells. To provide each compartment with its distinct properties, metabolic homeostasis and molecular composition need to be precisely coordinated in a compartment-specific manner. Despite the importance of the endoplasmic reticulum (ER) as a platform for various biochemical reactions, such as protein synthesis, protein trafficking, and intracellular calcium control, the contribution of the ER to neuronal compartment-specific functions and plasticity remains elusive. Recent advances in the development of live imaging and serial scanning electron microscopy (sSEM) analysis have revealed that the neuronal ER is a highly dynamic organelle with compartment-specific structures. sSEM studies also revealed that the ER forms contacts with other membranes, such as the mitochondria and plasma membrane, although little is known about the functions of these ER-membrane contacts. In this review, we discuss the mechanisms and physiological roles of the ER structure and ER-mitochondria contacts in synaptic transmission and plasticity, thereby highlighting a potential link between organelle ultrastructure and neuronal functions.

Keywords: ER-mitochondria contact; endoplasmic reticulum; neurotransmission; serial scanning electron microscopy; synaptic plasticity

DOI: https://doi.org/10.2183/pjab.97.028

Nat Chem Biol. 2021 Dec 16.

Stepwise membrane binding of extended synaptotagmins revealed by optical tweezers.

Jinghua Ge, Xin Bian, Lu Ma, Yiying Cai, Yanghui Li, Jie Yang, Erdem Karatekin, Pietro De Camilli, Yongli Zhang.

Extended synaptotagmins (E-Syts) mediate lipid exchange between the endoplasmic reticulum (ER) and the plasma membrane (PM). Anchored on the ER, E-Syts bind the PM via an array of C2 domains in a Ca2+- and lipid-dependent manner, drawing the two membranes close to facilitate lipid exchange. How these C2 domains bind the PM and regulate the ER-PM distance is not well understood. Here, we applied optical tweezers to dissect PM binding by E-Syt1 and E-Syt2. We detected Ca2+- and lipid-dependent membrane-binding kinetics of both E-Syts and determined the binding energies and rates of individual C2 domains or pairs. We incorporated these parameters in a theoretical model to recapitulate salient features of E-Syt-mediated membrane contacts observed in vivo, including their equilibrium distances and probabilities. Our methods can be applied to study other proteins containing multiple membrane-binding domains linked by disordered polypeptides.

DOI: https://doi.org/10.1038/s41589-021-00914-3

Nature. 2021 Dec 15.

ER proteins decipher the tubulin code to regulate organelle distribution.

Pengli Zheng, Christopher J Obara, Ewa Szczesna, Jonathon Nixon-Abell, Kishore K Mahalingan, Antonina Roll-Mecak, Jennifer Lippincott-Schwartz, Craig Blackstone.

Organelles move along differentially modified microtubules to establish and maintain their proper distributions and functions1,2. However, how cells interpret these post-translational microtubule modification codes to selectively regulate organelle positioning remains largely unknown. The endoplasmic reticulum (ER) is an interconnected network of diverse morphologies that extends promiscuously throughout the cytoplasm3, forming abundant contacts with other organelles4. Dysregulation of endoplasmic reticulum morphology is tightly linked to neurologic disorders and cancer5,6. Here we demonstrate that three membrane-bound endoplasmic reticulum proteins preferentially interact with different microtubule populations, with CLIMP63 binding centrosome microtubules, kinectin (KTN1) binding perinuclear polyglutamylated microtubules, and p180 binding glutamylated microtubules. Knockout of these proteins or manipulation of microtubule populations and glutamylation status results in marked changes in endoplasmic reticulum positioning, leading to similar redistributions of other organelles. During nutrient starvation, cells modulate CLIMP63 protein levels and p180-microtubule binding to bidirectionally move endoplasmic reticulum and lysosomes for proper autophagic responses.

DOI: https://doi.org/10.1038/s41586-021-04204-9