Piecing Together the Patchwork of Contact Sites

Abstract

7Contact sites are places where two organelles join together to carry out a shared activity requiring 8 non--vesicular communication. A large number of contact sites have been discovered, and almost 9 any two organelles can contact each other. General rules about contacts include constraints on 10 bridging proteins, with only a minority of bridges physically creating contacts by acting as 11 "tethers". The downstream effects of contacts include changing the physical behaviour of 12 organelles, and also forming biochemically heterogeneous sub--domains. However, some functions 13 typically localised to contact sites, such as lipid transfer, have no absolute requirement to be 14 situated there. Therefore, the key aspect of contacts is the directness of communication, which 15 allows metabolic channelling and collective regulation. and Rouiller [1]. Afterwards contact sites were largely overlooked for 50 years [2], and are still 31missing from text books. The last decade has seen much progress, and there are many excellent 32 reviews that describe these developments as a whole [3,4], or at a single contact site [5] or for one 33 family of components [6]. This article has a dual focus: in this section we describe how almost 34 every pair of organelles now appears to form contacts (Figure 1, Key Figure); later we make 35 general inferences about contact site function. 36 37 Contacts formed by mitochondria, a second intracellular network 38Early on the ER appeared as a common partner to most other organelles, including mitochondria, 39 plasma membrane, endosomes/phagosomes/lysosomes, Golgi apparatus and lipid droplets. This 40 led us to suggest a model that all organelles had constitutive contacts with the ER, which acts as a 41 pan-cellular conduit for small metabolites such as Ca 2+ and lipids [2]. However, the demonstration 42 that many non-ER organelles directly contact each other has shown that our model was wrong. 43After the ER, a second intracellular reticulum is formed by mitochondria. Although mitochondria 44 vary in size and inter-connectedness, when viewed as a whole they can form an intracellular 45 network that is almost as extensive as the ER. Like the ER, the mitochondrial network contacts 46 most other organelles. Here we review the evidence for the different contacts formed by 47 mitochondria. 48Endosome/lysosome-mitochondrion 49 contacts between endo-/lysosomes and mitochondria have been seen in several mammalian cell 50 types, where they mediate direct traffic of material. In red blood cell precursors early endosomes 51 contact mitochondria to transfer endocytosed iron for mitochondrial heme synthesis [7]. In 52 hypoxic cancer cells similar contacts allow partial "kiss and run" fusion that transfers endocytic 53 3 proteolytic enzymes to mitochondria [8]. Contact sites have also been found in pigmenting cells 54 joining melanosomes, which are lysosome-related organelles, to mitochondria, possibly for 55 production of ATP close to sites of melanization [9]. 56The best characterised contacts ...

Advances on the Transfer of Lipids by Lipid Transfer Proteins

“…Virtually all intracellular TULIPs and LAMs studied so far are found at contact sites [25]. These are narrow (10–30 nm) gaps between organelles that can be spanned by individual proteins.…”

“…These are narrow (10–30 nm) gaps between organelles that can be spanned by individual proteins. Contact sites have been found between an increasingly wide range of organelles 25, 26, 27. They were already known to contain a range of LTPs, in particular and many OSBP-related proteins (ORPs, in yeast also called OSBP homologues, Osh), ceramide transfer protein (CERT), PITPs related to RdgB in flies (Nir in humans) [28], and possibly the glycolipid transfer protein four-phosphate adaptor protein-2 (also called FAPP2) [29].…”

Tubular lipid binding proteins (TULIPs) growing everywhere

“…Thus, all SMP domains are in proteins anchored to the cytosolic face of a membrane. More specifically, all SMP proteins target membrane contact sites where two organelles come very close to each other (see Box 1) [37], which is likely to be functionally important.

Membrane contact sites.The architecture of the intracellular world has gone through a quiet revolution in the last decade, with an increased recognition that most organelles interact physically with each other at contact sites [56], [76], [104]. This also applies to the pair of membranes in Gram-negative bacteria, as well their descendants in mitochondria and in chloroplasts.

…”

“…The architecture of the intracellular world has gone through a quiet revolution in the last decade, with an increased recognition that most organelles interact physically with each other at contact sites [56], [76], [104]. This also applies to the pair of membranes in Gram-negative bacteria, as well their descendants in mitochondria and in chloroplasts.…”

Meeting report – Emerging Concepts in Cell Organization

“…Thus, lipid transfer was given attention by many speakers (see also the section on 'lipids and neurodegeneration' below). Tim Levine (University College London, UK) discussed contact sites between organelles by highlighting the patchwork-type organization of contacts between any pair of organelles (Gatta and Levine, 2017). Tim also presented a bioinformatics approach to search for lipid-transport proteins that contain tubular lipid-binding (TULIP) domains, which revealed their great diversity.…”