Lupashin, Vladimir

Prydz, Kristian

Saraste, Jaakko

Wang, Yanzhuang

English

NORA - Norwegian Open Research Archives

Editorial: Golgi Dynamics in Physiological and Pathological Conditions

Bergen Open Research Archive (Univ. of Bergen)

EDITORIALpublished: 29 January 2020doi: 10.3389/fcell.2020.00007Frontiers in Cell and Developmental Biology | www.frontiersin.org 1 January 2020 | Volume 8 | Article 7Edited and reviewed by:Georg Haase,INSERM U1106 Institut deNeurosciences des Systèmes, France*Correspondence:Kristian Prydzkristian.prydz@ibv.uio.noVladimir Lupashinvvlupashin@uams.eduYanzhuang Wangyzwang@umich.eduJaakko Sarastejaakko.saraste@uib.noSpecialty section:This article was submitted toMembrane Traffic,a section of the journalFrontiers in Cell and DevelopmentalBiologyReceived: 08 December 2019Accepted: 10 January 2020Published: 29 January 2020Citation:Prydz K, Lupashin V, Wang Y andSaraste J (2020) Editorial: GolgiDynamics in Physiological andPathological Conditions.Front. Cell Dev. Biol. 8:7.doi: 10.3389/fcell.2020.00007Editorial: Golgi Dynamics inPhysiological and PathologicalConditionsKristian Prydz 1*, Vladimir Lupashin 2*, Yanzhuang Wang 3* and Jaakko Saraste 4*1Department of Biosciences, University of Oslo, Oslo, Norway, 2Department of Physiology and Biophysics, University ofArkansas for Medical Sciences, Little Rock, AR, United States, 3Department of Molecular, Cellular and DevelopmentalBiology, University of Michigan, Ann Arbor, MI, United States, 4Department of Biomedicine and Molecular Imaging Center,University of Bergen, Bergen, NorwayKeywords: Golgi apparatus, Golgi dynamics, Golgi structure, Golgi function, membrane traffickingEditorial on the Research TopicGolgi Dynamics in Physiological and Pathological ConditionsThe internal reticular apparatus, first reported in 1898, and later called the Golgi apparatus,was initially observed by Camillo Golgi after his refinement of the silver nitrate technique forstaining cells in the nervous system, for which he received the Nobel Prize in Physiology orMedicine in 1906. The true existence of the Golgi apparatus was, however, disputed for decades,and many scientists regarded it as a staining artifact (Palade and Claude, 1949). Only after theelectron microscope became a more generally available tool for cell biologists was the Golgiapparatus accepted as an authentic cellular structure, and its existence demonstrated in practicallyall eukaryotic cells, from yeast to man. However, for reasons that are not completely understood,the Golgi assumes various forms in different cell types, ranging from tubular networks or individualcisternae (budding yeast S. cerevisiae) to separate cisternal stacks (e.g., invertebrates and plants) anda ribbon-like structure of interconnected stacks (vertebrates). As reflected in this collection, muchof the recent efforts to define the mechanism of Golgi structure formation have been put on Golgistructural proteins including Golgins and GRASPs, actin and microtubule cytoskeletons, Rabs,and other GTPases, as well as certain other proteins (Ahat et al.; Egorov and Polishchuk; Lowe;Phuyal and Farhan; Satoh et al.; Shaik et al.). Although these proteins have their own characteristicfunctions, they coordinate with each other to maintain the structural and functional integrity ofthe Golgi.The fascinating structure of the Golgi stacks is partly determined by GRASP proteins whichalso participate in a number of additional cellular processes, such as unconventional secretionand autophagy (Ahat et al.). In vertebrate cells, the multiple stacks are further organized intothe Golgi ribbon, a continuous structure where the cisternal stacks are joined together by lateralconnections (Saraste and Prydz). Several proteins have been shown to be involved in the regulationof ribbon structure, among these GRASP55 and GRASP65 (Ahat et al.) and the tethering proteingiantin (Satoh et al.). Although the ribbon-like organization of the Golgi remains enigmatic, itis highly interesting with respect to certain pathological situations. Indeed, fragmentation of theGolgi ribbon is encountered in a number of neurological diseases (Caracci et al.; Makhoul et al.).Prydz et al. Golgi DynamicsThe consequences of Golgi structural abnormalities on itsfunction and cellular activities may vary in different experimentalor disease conditions. For example, knocking down the GRASPproteins accelerates intra-Golgi trafficking (Xiang et al., 2013;Lee et al., 2014), while inhibition of GM130 and p115 resultsin the accumulation of COPI vesicles and reduced membranetrafficking (Seemann et al., 2000). Similarly, Aβ (amyloid β)-induced Golgi reorganization in Alzheimer’s disease has beenproposed to increase APP (amyloid precursor protein) traffickingand Aβ production (Joshi et al., 2014), while GM130 knockoutslows down ER-Golgi trafficking, resulting in Purkinje neuronloss and ataxia in mice (Liu et al., 2017). In addition, boththe morphology (Makhoul et al.) and the internal environment(such as lumenal pH) of the Golgi apparatus are altered incancer cells, leading to changes in glycosylation (Kellokumpu).Future investigations of the cause and effect of Golgi defects indisease will undoubtedly yield exciting findings essential for theunderstanding of both Golgi function and disease development.Structural reorganization of the Golgi is also an integralpart of naturally occurring processes, as best demonstratedin the case of cell division. During the late G2 phase,as cells prepare for mitosis, the Golgi ribbon is unlinkedinto individual stacks, which subsequently undergo furtherdisassembly and vesiculation. In the course of these events,repositioning of Golgi elements is typically observed in theperinuclear region of many vertebrate cells, controlled by theduplicated centrosome and centrosome-nucleated microtubulesof the forming mitotic spindle (Mascanzoni et al.). Notably,the pulling apart of the centrosomes during the late G2/earlymitosis is accompanied by the evidently equal partitioning ofthe intermediate compartment (IC), a permanent membranenetwork that–unlike the Golgi stacks—keeps its propertiesduring mitosis (Saraste and Marie, 2018).The role of the Golgi apparatus as an important way stationin anterograde trafficking along the secretory pathway wasestablished during the 1960s and 1970s (see Farquhar andPalade, 1998, for a review), while retrograde transport via thisorganelle was described much later (Sandvig et al., 1992). Inaddition, the role of the Golgi apparatus as an “educational”site for glycoproteins, proteoglycans, and glycolipids is well-described and generally accepted. Accordingly, the majorityof newly synthesized proteins that enter the Golgi apparatusat its cis-side carry N-linked glycans of identical structure,but leave the trans-Golgi region equipped with highly diverseglycans, specific for the actual species, the cell type, as wellas the cell’s developmental stage or degree of differentiation(Fisher et al.; Akintayo and Stanley). The ability of varioustransiting cargo molecules to obtain a healthy output of theseand other Golgi modifications, however, requires mechanismsof membrane homeostasis and transport that are still subject toactive investigation and dispute (Mironov and Beznoussenko;Saraste and Prydz; Makhoul et al.; Pantazopoulou and Glick).Not only the evaluation of competing Golgi models (Mironovand Beznoussenko), but also performing mathematical modeling(Fisher et al.) can advance our understanding of how cargomolecules that enter the cis-face of the Golgi apparatus aremodified during Golgi transit, and how their final structures willturn out. The ongoing attempts to correlate the structural andfunctional dynamics of the Golgi apparatus are still absolutelyrequired to achieve this goal. While the mechanisms of howdifferent cargo molecules traffic through the Golgi stacks are stillunder debate, it remains even less clear how precise localizationof Golgi resident proteins is achieved within the polarized stacks.The swarms of COPI vesicles observed at the outskirts ofthe Golgi membranes are essential for normal Golgi function,although their engagement is still not fully understood due topartial knowledge of their exact cargo selection and composition,places of origin and destination, delivery mechanisms,interaction partners and regulatory modes (Pantazopoulou andGlick; Luo and Boyce; D’Souza et al.). The Rho GTPase Cdc42is involved in the regulation of actin filament- and microtubule-dependent Golgi positioning, in addition to interacting withCOPI vesicles or tubules, thus potentially promoting anterogradetransport toward the leading edge of migrating cells (Phuyal andFarhan). The trafficking capacity of these transport intermediatescan be regulated in a number of ways (Luo and Boyce). Forexample, defects in the octameric COG complex that functionsas a tether in COPI vesicle-mediated retrograde transport,not only affect traditional Golgi functions like glycosylationand sorting, but also exert effects elsewhere in the cell, inparticular within the endo-lysosomal system (D’Souza et al.).Knockdown of the COG3 subunit of COG–or the ZW10 subunitof NRZ/Dsl1, another member of the CATCHR family ofmultisubunit tethering complexes–leads to the dispersal of theGolgi apparatus throughout the cytoplasm of metazoan cells(Zolov and Lupashin, 2005; Sun et al., 2007) in a process thatrequires both Rab GTPases and kinesin motor proteins (Liuet al.). The dynamic nature of the Golgi apparatus is underlinedby the fact that while a large number of proteins are requiredto maintain its normal organization, treatments affecting asingle structural or machinery component are often sufficientto destabilize its structure, as exemplified by the EGFR tyrosinekinase inhibitors BML-265 and AG1478 (Boncompain et al.).In addition to the COPI transport machineries, the dynamicnature and maintenance of the Golgi apparatus crucially dependon efficient mechanisms of membrane fusion and fission.Both processes are influenced by lipid modifying enzymes,such as acylglycerophosphate acyltransferases (Zhukovskyet al.), membrane curvature-sensing proteins, and fissioninducing-proteins (Zhukovsky et al.). To understand Golgifunction completely it will be important to reconstitute Golgifusion and fission in vitro using purified components andendogenous cargo.A question that has been touched upon, but is far frombeing solved, is whether all the stacks in a Golgi ribbon handlethe same cargo and have identical enzymatic contents to carryout the same protein and lipid modifications. While the non-linked, wide-spread Golgi stacks in Drosophila cells differ intheir enzymatic repertoire (Yano et al., 2005), the apical andbasolateral routes in mammalian epithelial MDCK cells havealso been shown to treat the same cargo molecule differently(Prydz et al., 2008). A related question is whether there maybe lateral segregation of cargo within cisternae of the sameGolgi stack. Interestingly, this was recently shown to be theFrontiers in Cell and Developmental Biology | www.frontiersin.org 2 January 2020 | Volume 8 | Article 7Prydz et al. Golgi Dynamicscase for HeLa cells, where two proteins heading for the endo-lysosomal system gradually underwent lateral segregation whilepassing through the Golgi (Chen et al., 2017). Here, the paper byErnst et al. discusses recent findings showing that acylation caninfluence the lateral positioning of proteins in Golgi cisternae,and as a consequence, their anterograde transport efficiency(Ernst et al.). While anterograde transport of cargo also takesplace after the stacks of the Golgi ribbon have been dispersed,for instance, due to breakdown of microtubules, an intact ribbondoes seem to be important for the transport of large cargomolecules (Lavieu et al., 2014). In a new view of the Golgi ribbon,the non-compact zones linking the cisternal stacks are jointlyoccupied by the permanent IC elements and recycling endosomes(RE). As mentioned above, as a prelude for cell division, thestacks that undergo reversible break-down disconnect fromthese centrosome-linked compartments, which as a consequencewould be allowed move to the spindle poles for partitioning intothe forming daughter cells (Saraste and Marie, 2018; Saraste andPrydz).Indeed, the Golgi apparatus is in intimate communicationwith both pre- and post-Golgi compartments. A number ofimportant proteins recycle between the endoplasmic reticulum(ER) and the Golgi apparatus. YIPFα1A, a member of the YIPFprotein family, functions at ER exit sites and interacts with COPIIcomponents, but can also localize to the IC and cis-Golgi, interactwith YIPβ1A, and recycle back to the ER (Shaik et al.). Membersof the CREB3 family of transcription factors move from the ERto the Golgi apparatus when the cell receives a proper signal.The activation of these proteins in the Golgi apparatus is basedon two sequential proteolytic cleavage events. Upon cleavage, theN-terminal portions of the proteins, which are localized to thecytoplasmic side of the Golgi membrane, are released and becomefree to move into the nucleus (Sampieri et al.).At the trans-side of the Golgi stacks, the trans-Golgi network(TGN) is an important site for Golgi exit of cargo moleculesdestined for various organelles of the endomembrane systemand different plasma membrane domains. With the continuousimprovement of the resolution of fluorescence-based lightmicroscopes, it is now possible to observe the segregation ofvarious cargo molecules and the membrane carriers that exit theGolgi at the level of the TGN (Huang et al.).To fully (or at least better) understand the Golgi apparatusin various physiological and pathological conditions, one hasto examine this organelle in a variety of tissues at differentstages of differentiation, development or degeneration, forinstance in neuronal (Caracci et al.; Rabouille and Haase,2016) and muscle cells (Oddoux et al.). This is important tounderstand the adaptability of the Golgi apparatus to the cellularrequirements, ensuring a healthy glycan output, as exemplifiedin this collection by the analysis of glycans of oocytes andsperm cells (Akintayo and Stanley). Equally important is to studya growing number of genetic diseases—such as the Aarskog-Scott syndrome (Egorov and Polishchuk), a faciogenital dysplasiacaused by mutations in a GEF protein (FGD1) regulating theRho GTPase Cdc42–that are found to affect Golgi structureand function.Altogether, topical reviews, hypothesis and theory articles, andoriginal studies in this collection illustrate our recent progressin understanding Golgi biology, and also outline a specificset of yet unanswered Golgi-related questions. For example,exactly how do cargo and resident proteins travel to, throughand out of the Golgi? What are the exact modes, carriersand molecular machineries of bi-directional Golgi trafficking?How are Golgi structure and its various functions modifiedduring normal (differentiation, development, etc.) and abnormal(diseases, drugs, pathogens, etc.) circumstances?AUTHOR CONTRIBUTIONSKP, VL, YW, and JS prepared and wrote the manuscript.FUNDINGThis work was supported by the NIH Grant GM083144 to VLand by the National Institute of Health (Grants GM112786,GM105920, and GM130331), MCubed and the FastforwardProtein Folding Disease Initiative of the University of Michiganto YW.REFERENCESChen, Y., Gershlick, D. C., Park, S. Y., and Bonifacino, J. S. (2017). Segregationin the Golgi complex precedes export of endolysosomal proteins in distincttransport carriers. J. Cell Biol. 216, 4141–4151. doi: 10.1083/jcb.201707172Farquhar, M. G., and Palade, G. E. (1998). The Golgi apparatus:100 years of progress and controversy. Trends Cell Biol. 8, 2–10.doi: 10.1016/S0962-8924(97)01187-2Joshi, G., Chi, Y., Huang, Z., and Wang, Y. (2014). Aβ-induced Golgifragmentation in Alzheimer’s disease enhances Aβ production. Proc. Natl. Acad.Sci. U.S.A. 111, E1230–E1239. doi: 10.1073/pnas.1320192111Lavieu, G., Dunlop, M. H., Lerich, A., Zheng, H., Bottanelli, F., and Rothman,J. E. (2014). The Golgi ribbon structure facilitates anterograde transportof large cargoes. Mol. Biol. Cell 25, 3028–3036. doi: 10.1091/mbc.e14-04-0931Lee, I., Tiwari, N., Dunlop, M. H., Graham, M., Liu, X., and Rothman, J. E. (2014).Membrane adhesion dictates Golgi stacking and cisternal morphology.Proc. Natl. Acad. Sci. U.S.A. 111, 1849–1854. doi: 10.1073/pnas.1323895111Liu, C., Mei, M., Li, Q., Roboti, P., Pang, Q., Ying, Z., et al. (2017). Loss ofthe golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxiain mice. Proc. Natl. Acad. Sci. U.S.A. 114, 346–351. doi: 10.1073/pnas.1608576114Palade, G. E., and Claude, A. (1949). The nature of the Golgi apparatus;identification of the Golgi apparatus with a complex of myelin figures. J.Morphol. 85, 71–111. doi: 10.1002/jmor.1050850104Prydz, K., Dick, G., and Tveit, H. (2008). Howmany ways through the Golgi maze?Traffic 9, 299–304. doi: 10.1111/j.1600-0854.2007.00690.xRabouille, C., and Haase, G. (2016). Editorial: Golgi pathologyin neurodegenerative diseases. Front. Neurosci. 9:489.doi: 10.3389/fnins.2015.00489Sandvig, K., Garred, O., Prydz, K., Kozlov, J. V., Hansen, S. H., and Van Deurs,B. (1992). Retrograde transport of endocytosed Shiga toxin to the endoplasmicreticulum. Nature 358, 510–512. doi: 10.1038/358510a0Frontiers in Cell and Developmental Biology | www.frontiersin.org 3 January 2020 | Volume 8 | Article 7Prydz et al. Golgi DynamicsSaraste, J., and Marie, M. (2018). Intermediate compartment (IC): from pre-Golgivacuoles to a semi-autonomous membrane system. Histochem. Cell Biol. 150,407–430. doi: 10.1007/s00418-018-1717-2Seemann, J., Jokitalo, E. J., and Warren, G. (2000). The role of thetethering proteins p115 and GM130 in transport through the Golgiapparatus in vivo. Mol. Biol. Cell 11, 635–645. doi: 10.1091/mbc.11.2.635Sun, Y., Shestakova, A., Hunt, L., Sehgal, S., Lupashin, V., and Storrie, B. (2007).Rab6 regulates both ZW10/RINT-1 and conserved oligomeric Golgi complex-dependent Golgi trafficking and homeostasis. Mol. Biol. Cell 18, 4129–4142.doi: 10.1091/mbc.e07-01-0080Xiang, Y., Zhang, X., Nix, D. B., Katoh, T., Aoki, K., Tiemeyer, M.,et al. (2013). Regulation of protein glycosylation and sorting by theGolgi matrix proteins GRASP55/65. Nat. Commun. 4:1659. doi: 10.1038/ncomms3310Yano, H., Yamamoto-Hino, M., Abe, M., Kuwahara, R., Haraguchi, S., Kusaka,I., et al. (2005). Distinct functional units of the Golgi complex in Drosophilacells. Proc. Natl. Acad. Sci. U.S.A. 102, 13467–13472. doi: 10.1073/pnas.0506681102Zolov, S. N., and Lupashin, V. V. (2005). Cog3p depletion blocks vesicle-mediated Golgi retrograde trafficking in HeLa cells. J. Cell Biol. 168, 747–759.doi: 10.1083/jcb.200412003Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2020 Prydz, Lupashin, Wang and Saraste. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Cell and Developmental Biology | www.frontiersin.org 4 January 2020 | Volume 8 | Article 7

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Editorial: Golgi Dynamics in Physiological and Pathological Conditions

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