cells Review Closing the Gap: Membrane Contact Sites in the Regulation of Autophagy Verena Kohler 1 , Andreas Aufschnaiter 2 and Sabrina Büttner 1,3,* 1 Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden; [email protected] 2 Department of Biochemistry and Biophysics, Stockholm University, 106 91 Stockholm, Sweden; [email protected] 3 Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria * Correspondence: [email protected] Received: 17 April 2020; Accepted: 7 May 2020; Published: 9 May 2020 Abstract: In all eukaryotic cells, intracellular organization and spatial separation of incompatible biochemical processes is established by individual cellular subcompartments in form of membrane-bound organelles. Virtually all of these organelles are physically connected via membrane contact sites (MCS), allowing interorganellar communication and a functional integration of cellular processes. These MCS coordinate the exchange of diverse metabolites and serve as hubs for lipid synthesis and trafficking. While this of course indirectly impacts on a plethora of biological functions, including autophagy, accumulating evidence shows that MCS can also directly regulate autophagic processes. Here, we focus on the nexus between interorganellar contacts and autophagy in yeast and mammalian cells, highlighting similarities and differences. We discuss MCS connecting the ER to mitochondria or the plasma membrane, crucial for early steps of both selective and non-selective autophagy, the yeast-specific nuclear–vacuolar tethering system and its role in microautophagy, the emerging function of distinct autophagy-related proteins in organellar tethering as well as novel MCS transiently emanating from the growing phagophore and mature autophagosome. Keywords: autophagy; ER–mitochondria encounter structure; ERMES; lipophagy; membrane contact sites; mitochondria-associated membranes; MAMs; mitophagy; nucleus–vacuole junction; pexophagy; piecemeal microautophagy of the nucleus 1. Introduction Intracellular compartmentalization in form of membrane-bound organelles represents a defining feature of eukaryotic cells. This spatial separation is a prerequisite for the generation of dedicated microenvironments to accommodate incompatible biochemical reactions. At the same time, efficient communication systems between individual organelles need to be in place to maintain cellular homeostasis, which is facilitated either via vesicular transport or direct contact between two organelles at so-called membrane contact sites (MCS) [1,2]. MCS have been described to govern essential cellular functions, including lipid metabolism and the transfer of small signaling molecules, including calcium ions (Ca2+)[3]. MCS can be classified as contacts between either identical (homotypic) or different (heterotypic) organelles [1]. According to recent guidelines, MCS are defined by (i) the presence of protein–protein or protein–lipid interactions that mediate tethering forces between the membranes, (ii) a lack of membrane fusion and fusion intermediates, (iii) a specific function of the contact, and (iv) a defined proteome and lipidome required for all previously mentioned definitions [1]. While MCS between virtually all organelles have been identified in recent years [4,5], a large number of heterotypic MCS involve the endoplasmic reticulum (ER) [6,7], reflecting the important role of the ER for Cells 2020, 9, 1184; doi:10.3390/cells9051184 www.mdpi.com/journal/cells CellsCells2020 2020, 9,, 11849, x FOR PEER REVIEW 2 of2 22 of 22 years [4,5], a large number of heterotypic MCS involve the endoplasmic reticulum (ER) [6,7], cellularreflecting metabolism the important and homeostasis. role of the TheER for molecular cellular architecture metabolism ofand distinct homeostasis. MCS seems The tomolecular be (at least inarchitecture part) evolutionary of distinct conserved, MCS seems and to thebe (at complex least in communicationpart) evolutionary networks conserved, established and the complex via MCS contributecommunication to the coordinated networks adaptionestablished of participatingvia MCS contribute organelles toto dithefferent coordinated environmental adaption challenges of acrossparticipating the eukaryotic organelles kingdom to different [4]. Accumulating environmenta evidencel challenges indicates across the that eukaryotic MCS play kingdom a decisive [4]. role inAccumulating regulating the evidence breakdown indicates of cellular that materialMCS play via a autophagydecisive role in in both regulating yeast and the higher breakdown eukaryotic of organisms.cellular material While via an intricateautophagy connection in both yeast between and higher autophagy eukaryotic and distinctorganisms. processes While an governed intricate by MCS—suchconnection as between Ca2+ signaling autophagy and and lipid distinct metabolism—is processes governed well established by MCS—such [8–11], recentas Ca2+ studies signaling suggest and a morelipid direct metabolism—is involvement well of MCS established in the regulation [8–11], recent of autophagy. studies suggest Indeed, a all more major direct subtypes involvement of autophagy, of includingMCS in macro-the regulation and microautophagy of autophagy. Indeed, (Figure 1all) as ma welljor subtypes as respective of autophagy, cargo-selective including and non-selectivemacro- and (bulk)microautophagy autophagic subforms,(Figure 1) as have well been as respective to some extendcargo-selective connected and tonon-selective MCS [12–16 (bulk)]. As autophagyautophagic is generallysubforms, described have been as ato cytoprotective some extend connected mechanism to MCS that mediates[12–16]. As cellular autophagy health is generally and longevity, described and its as a cytoprotective mechanism that mediates cellular health and longevity, and its dysregulation is dysregulation is associated with a wide range of human diseases [17], the emerging interplay between associated with a wide range of human diseases [17], the emerging interplay between autophagy and autophagy and MCS might have important physiological as well as pathophysiological implications. MCS might have important physiological as well as pathophysiological implications. While we While we intend to give a brief overview of selected aspects of autophagy that we touch upon in later intend to give a brief overview of selected aspects of autophagy that we touch upon in later sections, sections, a comprehensive description of this multi-faceted process can be found in several excellent a comprehensive description of this multi-faceted process can be found in several excellent reviews reviews(e.g., [12,18–24]). (e.g., [12,18 –24]). FigureFigure 1. 1.Schematic Schematic overview overview of of macromacro oror bulk-bulk- (blue)-(blue)- and microautophagy microautophagy (y (yellow).ellow). For For a general a general descriptiondescription of of autophagy, autophagy, pleaseplease seesee main text. text. PMN PMN = piecemeal= piecemeal microautophagy microautophagy of the of nucleus., the nucleus, P P == peroxisome, M M == mitochondria,mitochondria, LD LD = lipid= lipid droplet. droplet. TheThe core core molecular molecular machinery machinery governing governing autophagy autophagy is highlyis highly conserved conserved from from simple simple single-celled single- eukaryotescelled eukaryotes like the like baker’s the baker’s yeast Saccharomyces yeast Saccharomyces cerevisiae cerevisiaeup to up complex to complex multicellular multicellular organisms organisms like humanslike humans [13,25]. [13,25]. During During macroautophagy, macroautophagy, cargo cargo is sequestered is sequestered into a into double-membraned a double-membraned vesicle vesicle termed autophagosome,termed autophagosome, which subsequently which subsequently fuses with fuses the lysosome with the orlysosome the yeast orcounterpart, the yeast counterpart, the vacuole the [26 ]. vacuole [26]. This involves a series of tightly-regulated steps, including initiation of the so-called This involves a series of tightly-regulated steps, including initiation of the so-called phagophore phagophore (or isolation membrane), its elongation with lipid resources and autophagosome (or isolation membrane), its elongation with lipid resources and autophagosome formation, fusion formation, fusion with the lysosome/vacuole, degradation of the cargo by soluble hydrolases, and with the lysosome/vacuole, degradation of the cargo by soluble hydrolases, and finally recycling of finally recycling of macromolecules (Figure 1). The lipid resources required for phagophore macromolecules (Figure1). The lipid resources required for phagophore initiation /elongation are initiation/elongation are suggested to originate from different organelles [13,22,23]. During selective suggestedforms of to macroautophagy, originate from di adaptorfferent organelles proteins intera [13,22ct,23 with]. During components selective of forms the core of macroautophagy, machinery of adaptorautophagy proteins as well interact as with with a components series of receptors of the core to target machinery the respective of autophagy organelle as well to asthe with expanding a series of receptorsphagophore to target membrane the respective ([22,27]; organelle Figure 1). to Microautophagy the expanding phagophorerefers to the membranedirect engulfment ([22,27 ];of Figure cargo1 ). Microautophagyinto the vacuole/lysosome refers to the via direct membrane engulfment invagina of cargotions and