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ER-Phagy at a Glance Paolo Grumati1,*, Ivan Dikic1,2,‡ and Alexandra Stolz2,*

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ER-Phagy at a Glance Paolo Grumati1,*, Ivan Dikic1,2,‡ and Alexandra Stolz2,* © 2018. Published by The Company of Biologists Ltd | Journal of Cell Science (2018) 131, jcs217364. doi:10.1242/jcs.217364 CELL SCIENCE AT A GLANCE ER-phagy at a glance Paolo Grumati1,*, Ivan Dikic1,2,‡ and Alexandra Stolz2,* ABSTRACT function in response to ER stress signals. This task sharing reflects Selective autophagy represents the major quality control mechanism the complexity of the ER in terms of biological functions and that ensures proper turnover of exhausted or harmful organelles, morphology. In this Cell Science at a Glance article and the among them the endoplasmic reticulum (ER), which is fragmented accompanying poster, we summarize the most recent findings and delivered to the lysosome for degradation via a specific type of about ER-phagy in yeast and in mammalian cells. autophagy called ER-phagy. The recent discovery of ER-resident KEY WORDS: Autophagy, CCPG1, FAM134B, RTN3, SEC62, proteins that bind to mammalian Atg8 proteins has revealed that the Endoplasmic reticulum selective elimination of ER involves different receptors that are specific for different ER subdomains or ER stresses. FAM134B (also known as RETREG1) and RTN3 are reticulon-type proteins that are Introduction able to remodel the ER network and ensure the basal membrane The endoplasmic reticulum (ER) is the largest membrane-bound turnover. SEC62 and CCPG1 are transmembrane ER receptors that organelle in eukaryotic cells. Its complex morphology, which involves sheets, tubules and matrices (Chen et al., 2013; Friedman and Voeltz, 2011; Nixon-Abell et al., 2016), mirrors its diverse roles 1Institute of Biochemistry II, Goethe University Frankfurt - Medical Faculty, in a variety of physiological processes including autophagy University Hospital, 60590 Frankfurt am Main, Germany. 2Buchmann Institute (Baumann and Walz, 2001; Lamb et al., 2013; Phillips and for Molecular Life Sciences, Goethe University Frankfurt – Riedberg Campus, Voeltz, 2016). How the elaborate ER network is generated, 60438 Frankfurt am Main, Germany. *These authors contributed equally to this work maintained, disassembled and restored is still a matter of ‡ investigation. ER tubules are extremely dynamic and constantly Author for correspondence ([email protected]) elongate, retract, fuse and slide along the cytoskeleton (Goyal and I.D., 0000-0001-8156-9511 Blackstone, 2013; Nixon-Abell et al., 2016; Shibata et al., 2009). Journal of Cell Science 1 CELL SCIENCE AT A GLANCE Journal of Cell Science (2018) 131, jcs217364. doi:10.1242/jcs.217364 ER sheets are less mobile but still have the capacity to enlarge in provided below and on the poster. Many more selective autophagy response to biological stimuli and shrink back to the original size pathways exist, including those essential for the maintenance and after the stress is solved (Lu et al., 2009; Wang et al., 2013). The turnover of other cellular organelles than the ER, but these will not ratio between sheets and tubules, as well as the formation of the ER be further addressed in this article. network is finely regulated by the oligomerization and spatial distribution of specific ER-membrane-bound proteins (Chen et al., Selective autophagy pathways 2012; Hu et al., 2011, 2009; Orso et al., 2009; Voeltz et al., 2006) Selective autophagy facilitates the targeted elimination of specific (see poster). organelles or cargos through the action of specific autophagy ER function and morphology are intimately linked to autophagy receptors, which recruit and sequester cargo into autophagosomes (Lamb et al., 2013). Macro-autophagy (hereafter referred to as (Stolz et al., 2014). Autophagy receptors often belong to a specific autophagy) is a catabolic process that involves the engulfment of organelle proteome and their characteristic feature is the ability to cellular material by a double-membraned structure, the phagophore, directly bind to the LC3/GABARAP family members [LC3A, which eventually closes to form a vesicle called the autophagosome LC3B, LC3C (also known as MAP1LC3A, MAP1LC3B and that sequesters the cargo inside. The autophagosome then fuses with MAP1LC3A, respectively), GABARAP, GABARAP-L1 and the lysosome to degrade the cargo. Of note, two other types of GABARAP-L2; Atg8 in yeast] through a LC3-interacting region autophagy have been described: micro-autophagy and chaperone- (LIR; AIM for Atg8-interacting motif in yeast), as well as the mediated autophagy (CMA) and both processes do not require autophagic cargo (Rogov et al., 2014, 2017). Because of their autophagosome formation. Invagination of the lysosome/vacuole interaction with the ATG8 family, classical autophagy receptors are membrane during micro-autophagy directly engulfs small cytosolic continuously degraded in the lysosome resulting in low basal levels. components (Sahu et al., 2011). In contrast, in CMA, cytosolic Genetic inactivation of specific autophagy receptors abolishes the proteins containing a KFERQ motif are recognized by the removal of the target organelle, but it does not affect other forms of chaperone protein heat shock cognate 70 (HSC70; also known as selective autophagy or unspecific macro-autophagy (Rogov et al., HSPA8) and directly translocate across the lysosomal membrane 2014; Stolz et al., 2014). Autophagy receptors may also accomplish (Orenstein and Cuervo, 2010). In response to starvation, autophagy other biological functions not necessarily related to autophagy. is mainly considered a bulk process that unselectively degrades Some examples are the mitophagy receptors prohibitin 2 (PHB2) cellular material to meet the energy needs of cells (Tooze and and FUNDC1 (Liu et al., 2012; Wei et al., 2017). PHB2 is an inner Yoshimori, 2010). However, autophagy can also selectively mitochondria membrane protein involved in the control of the target distinct organelles and cellular structures that are damaged functional integrity of the organelle (Merkwirth and Langer, 2009), and/or need to be turned over (Rogov et al., 2014). Although ER while FUNDC1 maintains ER–mitochondria interactions (Muñoz membranes had been observed inside lysosomes after phenobarbital and Zorzano, 2017). Below, we will discuss the pathways of treatment (Bolender and Weibel, 1973) or in autophagosomes ER-phagy that have been so far described in yeast and mammals. in yeast (Hamasaki et al., 2005), the ER was initially primarily considered as the major source of autophagosome membranes ER-phagy in yeast (Hayashi-Nishino et al., 2009; Ylä-Anttila et al., 2009), and ER In yeast, the ER provides membranes for autophagosomes and, at membranes inside the autophagosomes were seen as an effect of the the same time, is itself a target of autophagy. The term ER-phagy general autophagy process due to bulk engulfment of the cytosol. was used for the first time by Peter Walter’s group in describing Only in the past few years, has the specific elimination of the ER how, within the unfolded protein response (UPR), ER whorls been classified as a selective form of autophagy (denoted become selectively degraded by the vacuole (Bernales et al., 2006; ER-phagy) and specific receptors have been characterized. Schuck et al., 2009). During UPR conditions, the ER significantly Various organelles have been shown to provide membrane for enlarges its volume and membrane content. However, soon after, autophagosome formation (Bodemann et al., 2011; Hailey et al., cells start to re-establish the initial ER homeostasis by eliminating 2010; Ravikumar et al., 2010); nevertheless, the major source of superfluous membrane via vacuolar degradation (Schuck et al., autophagic membrane, which subsequently forms autophagosomes, 2014). This can also function as a detoxification system in which is the ER (Lamb et al., 2013). Autophagic membrane can be aggregated or otherwise unwanted proteins are constricted to generated from the entire ER body, as well as from the contact defined ER compartments and subsequently eliminated by the sites between ER and mitochondria (mitochondria-associated vacuole (Cebollero et al., 2012; Yorimitsu and Klionsky, 2007). The membranes; MAMs) or between ER and plasma membrane initial hypothesis was that the utilized autophagy pathway may (Hamasaki et al., 2013; Nascimbeni et al., 2017). Moreover, the differ depending on the initial stress and on the affected organism ER is the natural harbor of many proteins of the autophagy (Bernales et al., 2006; Ogata et al., 2006; Yorimitsu et al., 2006). machinery. Autophagic membranes originate from ER structures Initially, the ER whorls formed upon treatment with DTT and called omegasomes, which are enriched in the phospholipid tunicamycin were thought to be degraded through autophagosomes. phosphatidylinositol 3-phosphate [PI(3)P] as well as the PI(3)P- However, later studies from the same laboratory showed the binding protein DFCP1 (also known as ZFYVE1) (Axe et al., 2008) dispensability of the typical core autophagy machinery, with the (see poster). Controlled assembly of the phosphoinositide 3-kinase cargo being directly absorbed by the vacuole via the micro- (PI3K) complex is therefore critical for autophagosome formation, autophagy pathway (Schuck et al., 2014). More recently, it has been as PI(3)P recruits and anchors several downstream factors of the shown that ER fragments can also be sequestered into Atg8-positive autophagy machinery (Matsunaga et al., 2010; Molejon et al., 2013; autophagosomes upon nutrient starvation or TOR inhibition by Polson et al., 2010). Moreover, the LC3 conjugation machinery (see rapamycin (Mochida
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