Foreword to C. Th. Dimaras Annual Lecture, 2019

Foreword to C. Th. Dimaras Annual Lecture, 201

Nietzsche and Heraclitus: Notes on Stars without an Atmosphere

I awake estranged from everyone. Words have lost their meaning; they sound indifferent and homonymous. The word No appears to mean Yes, or rather: Yes and No are malleable, ephemeral, and transparent. A decades-old or perhaps centuries-old movement of miry clay has resulted in a miscarriage of words. Iinquire whether anyone still holds the resources needed for a direct, sincere affirmation of life—a Yes that is definitively and essentially affirmative—or a No that is definitively and essentially negative—words bursting forth splendour like a crystal. I am told that formulations of this sort are incomprehensible; they are too metaphorical and, in the end, nonsensical, at least according to the elenctic criteria of analytical philosophy and common sense..

New kid on the block: lipid droplets in the nucleus.

The regulation of lipid homeostasis is essential for normal cell physiology, and its disruption can lead to disease. Lipid droplets (LDs) are ubiquitous organelles dedicated to storing nonpolar lipids that are used for metabolic energy production or membrane biogenesis. LDs normally emerge from, and associate with, the endoplasmic reticulum and interact with other cytoplasmic organelles to deliver the stored lipids. Recently, LDs were found to reside also at the inner side of the nuclear envelope and inside the nucleus in yeast and mammalian cells. This unexpected finding raises fundamental questions about the nature of the inner nuclear membrane, its connection with the endoplasmic reticulum and the pathways of LD formation. In this viewpoint, we will highlight recent developments relating to these questions and discuss possible roles of LDs in nuclear physiology

Lipid droplet-organelle interactions: emerging roles in lipid metabolism.

Cellular homeostasis depends on the precisely coordinated use of lipids as fuels for energy production, building blocks for membrane biogenesis or chemical signals for intra-cellular and inter-cellular communication. Lipid droplets (LDs) are universally conserved dynamic organelles that can store and mobilize fatty acids and other lipid species for their multiple cellular roles. Increasing evidence suggests that contact zones between LDs and other organelles play important roles in the trafficking of lipids and in the regulation of lipid metabolism. Here we review recent advances regarding the nature and functional relevance of interactions between LDs and other organelles-particularly the endoplasmic reticulum (ER), LDs, mitochondria and vacuoles-that highlight their importance for lipid metabolism.This work was supported by an MRC Senior Non-Clinical Fellowship (to SS) and a Wellcome Trust Senior Clinical Fellowship (to DBS).This is the accepted manuscript. The final version is available at http://www.sciencedirect.com/science/article/pii/S0955067415000575

TMF is a golgin that binds Rab6 and influences Golgi morphology

BACKGROUND: Golgins are coiled-coil proteins associated with the Golgi apparatus, that are believed to be involved in the tethering of vesicles and the stacking of cisternae, as well as other functions such as cytoskeletal association. Many are peripheral membrane proteins recruited by GTPases. Several have been described in animal cells, and some in yeast, but the relationships between golgins from different species can be hard to define because although they share structural features, their sequences are not well conserved. RESULTS: We show here that the yeast protein Sgm1, previously shown to be recruited to the Golgi by the GTPase Ypt6, binds to Ypt6:GTP via a conserved 100-residue coiled-coil motif that can be identified in a wide range of eukaryotes. The mammalian equivalent of Sgm1 is TMF/ARA160, a protein previously identified in various screens as a putative transcription or chromatin remodelling factor. We show that it is a Golgi protein, and that it binds to the three known isoforms of the Ypt6 homologue Rab6. Depletion of the protein by RNA interference in rat NRK cells results in a modest dispersal of Golgi membranes around the cell, suggesting a role for TMF in the movement or adherence of Golgi stacks. CONCLUSION: We have identified TMF as an evolutionarily conserved golgin that binds Rab6 and contributes to Golgi organisation in animal cells

Function of lipid droplet-organelle interactions in lipid homeostasis

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.Recent work from our group referred to in this review was supported by the MRC (G0701446) and the Wellcome Trust (108042/ Z/15/Z). The Cambridge Institute for Medical Research is supported by Wellcome Trust Strategic Award 100140

Temporal and spatial regulation of the phosphatidate phosphatases lipin 1 and 2

Peer reviewedPublisher PD

Spatial distribution of lipid droplets during starvation: Implications for lipophagy.

Survival during starvation depends largely on metabolic energy, which is stored in the form of neutral lipids in specialized organelles known as lipid droplets. The precursors for the synthesis of neutral lipids are also used for membrane biogenesis, which is required for cell growth and proliferation. Therefore cells must possess mechanisms to preferentially channel lipid precursors toward either membrane synthesis or lipid droplet storage, in response to nutrient status. How this partitioning is spatially regulated within the endoplasmic reticulum (ER) where lipid droplets co-localize, remains poorly understood. We have recently shown that at the onset of starvation lipid droplets concentrate at a perinuclear ER subdomain flanking the nucleus-vacuole junction (NVJ) and that this is crucial for maintaining proper nuclear shape and ER membrane organization. Here we show that disruption of the NVJ does not block the translocation and internalization of lipid droplets into the vacuole for their degradation, which takes place at later stages of starvation. We propose that alternative pathways of lipid droplet translocation from the ER to the vacuole may exist to enable stationary phase-induced lipophagy.This work was supported by the Medical Research Council (G0701446) and the Wellcome Trust (108042/Z/15/Z)