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Stx5-Mediated ER-Golgi Transport in Mammals and Yeast

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cells Review Stx5-Mediated ER-Golgi Transport in Mammals and Yeast Peter TA Linders 1 , Chiel van der Horst 1, Martin ter Beest 1 and Geert van den Bogaart 1,2,* 1 Tumor Immunology Lab, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands 2 Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands * Correspondence: [email protected]; Tel.: +31-50-36-35230 Received: 8 July 2019; Accepted: 25 July 2019; Published: 26 July 2019 Abstract: The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) syntaxin 5 (Stx5) in mammals and its ortholog Sed5p in Saccharomyces cerevisiae mediate anterograde and retrograde endoplasmic reticulum (ER)-Golgi trafficking. Stx5 and Sed5p are structurally highly conserved and are both regulated by interactions with other ER-Golgi SNARE proteins, the Sec1/Munc18-like protein Scfd1/Sly1p and the membrane tethering complexes COG, p115, and GM130. Despite these similarities, yeast Sed5p and mammalian Stx5 are differently recruited to COPII-coated vesicles, and Stx5 interacts with the microtubular cytoskeleton, whereas Sed5p does not. In this review, we argue that these different Stx5 interactions contribute to structural differences in ER-Golgi transport between mammalian and yeast cells. Insight into the function of Stx5 is important given its essential role in the secretory pathway of eukaryotic cells and its involvement in infections and neurodegenerative diseases. Keywords: syntaxin 5; Golgi apparatus; endoplasmic reticulum; membrane trafficking; secretory pathway 1. Introduction The secretory pathway is essential for secretion of cytokines, hormones, growth factors, and extracellular matrix proteins, as well as for the delivery of receptors and transporters to the cell membrane and lytic proteins to endo-lysosomal compartments. Proteins destined for the secretory pathway are synthesized at the endoplasmic reticulum (ER) and subsequently transported to their destination by vesicular trafficking via the cis- to medial- to trans-Golgi cisternae and finally to the trans-Golgi network [1–3]. ER-Golgi transport has been mostly studied in mammalian cells and the yeast Saccharomyces cerevisiae, and although the basic mechanisms of this ER-Golgi trafficking are well conserved among eukaryotic cells, there are three pronounced differences between the yeast S. cerevisiae and mammalian cells (Figure1). The first di fference concerns the spatial organization of the Golgi apparatus. In most mammalian cell types, a single large Golgi apparatus is juxtaposed with the nucleus and surrounds the microtubule organizing center (MTOC) [2,4,5]. In contrast, in S. cerevisiae, the Golgi is organized into discrete cisternae, consisting of individual cisternae that are scattered throughout the cytoplasm, while in other yeast, such as budding Pichia pastoris and Schizosaccharomyces pombe, the Golgi is present as mini-stacks that are dispersed in the cytoplasm [4,5]. The second difference is the presence of an intermediate compartment between the ER and cis-Golgi in mammals called the ER-Golgi intermediate compartment (ERGIC) or vesicular-tubular cluster (VTC) [6]. Yeast does not have an ERGIC, and anterograde trafficking from the ER occurs directly to the cis-Golgi [7] via vesicles coated with the cage protein complex COPII, while retrograde trafficking in the reverse direction occurs Cells 2019, 8, 780; doi:10.3390/cells8080780 www.mdpi.com/journal/cells Cells 2019, 8, 780 2 of 16 via vesicles coated with COPI [2,4]. In mammalian cells, anterograde trafficking from the ER also occursCellsvia 2019 COPII-coated, 8, 780 vesicles, but in this case, proceeds to the ERGIC [2,4,5]. In mammalian2 of 16 cells, not only retrograde trafficking from the ERGIC back to the ER but also further anterograde trafficking anterograde trafficking from the ER also occurs via COPII-coated vesicles, but in this case, proceeds to the cis-Golgi might occur via COPI-coated vesicles [8]. A final difference in ER-Golgi trafficking is to the ERGIC [2,4,5]. In mammalian cells, not only retrograde trafficking from the ERGIC back to the the involvementER but also further of microtubules anterograde intrafficking mammalian to the cells,cis-Golgi but might not in occur yeast via [2, 4COPI-coated,5]. In this review,vesicles we[8]. argue thatA these final mechanisticdifference in ER-Golgi differences trafficking between is the mammals involvement and of yeast microtubules are partly in mammalian attributable cells, to one but of the centralnot in players yeast [2,4,5]. in ER-Golgi In this review, trafficking: we argue the SNAREthat these protein mechanistic syntaxin differences 5 (Stx5) between in mammals mammals and and its yeast orthologyeast are Sed5p. partly attributable to one of the central players in ER-Golgi trafficking: the SNARE protein syntaxin 5 (Stx5) in mammals and its yeast ortholog Sed5p. FigureFigure 1. 1.Schematic Schematicoverview overview of the early early secretory secretory pathway pathway in Saccharomyces in Saccharomyces cerevisiae cerevisiae (A) and(A ) and mammalianmammalian cells cells (B ().B). Abbreviations: Abbreviations: ER, endoplasmic endoplasmic reticulum; reticulum; ERES, ERES, endoplasmic endoplasmic reticulum reticulum exit exit sites;sites; ERGIC, ERGIC, endoplasmic endoplasmic reticulum-Golgireticulum-Golgi inte intermediatermediate compartment; compartment; MT, MT,microtubule; microtubule; MTOC, MTOC, microtubulemicrotubule organizing organizing center; center; TGN, TGN, transtrans-Golgi-Golgi network. network. 2. SNARE2. SNARE Proteins Proteins in in ER-Golgi ER-Golgi andand Intra-Golgi Transport Transport TheThe SNARE SNARE protein protein family family consists consists ofof aboutabout 38 members members in in humans humans and and about about 24 in 24 yeast in yeast and and is is responsible for most intracellular fusion events of organellar trafficking [9–11]. The central responsible for most intracellular fusion events of organellar trafficking [9–11]. The central hallmark of hallmark of SNARE proteins is the presence of one or two SNARE motifs of 50–70 residues in size. SNARE proteins is the presence of one or two SNARE motifs of 50–70 residues in size. Based on the Based on the structures of these motifs, SNAREs can be grouped into R-SNAREs, with an arginine structuresresidue of located these motifs,at the center SNAREs of the can SNARE-moti be groupedf, into andR-SNAREs, Qa-, Qb- and with Qc-SNAREs, an arginine with residue a central located at the centerglutamine of the residue SNARE-motif, [10,11]. Membrane and Qa-, fusion Qb- and requir Qc-SNAREs,es three or withfour acognate central SNARE glutamine proteins residue that [ 10,11]. Membranetogetherfusion contribute requires four threeSNARE or motifs, four cognate one of SNAREeach group proteins (R, Qa, that Qb, togetherQc). For contributemembrane fusion, four SNARE motifs,these one cognate of each SNARE group proteins (R, Qa, need Qb, to be Qc). anchored For membrane to both the donor fusion, membrane these cognate (e.g., COPII SNARE vesicle) proteins needand to beacceptor anchored membrane to both the(e.g., donor cis-Golgi) membrane via a (e.g.,C-terminal COPII transmembrane vesicle) and acceptor helix or membrane by lipid (e.g., cis-Golgi)modifications via a C-terminal [10,11]. SNAREs transmembrane in the donor helix membrane or by lipid are called modifications v-SNAREs [ (vesicular-SNAREs)10,11]. SNAREs in and the donor membraneSNAREs are in calledthe acceptor v-SNAREs membrane (vesicular-SNAREs) t-SNAREs (target-SNAREs). and SNAREs Cognate in the SN acceptorARE proteins membrane can form t-SNAREs a tight α-helical coiled-coil bundle, called the SNARE complex, which overcomes the energy barrier (target-SNAREs). Cognate SNARE proteins can form a tight α-helical coiled-coil bundle, called the of membrane fusion. In addition to this, the fusogenic activity of ER-Golgi SNAREs is tightly SNAREregulated complex, by numerous which overcomesinteracting proteins the energy and by barrier N-terminal-regulating of membrane fusion. motifs, Inwhich addition are present to this, the fusogenicon most activity SNAREs of [10,11]. ER-Golgi After SNAREs membrane is tightlyfusion, regulatedthe SNARE by complex numerous is disassembled interacting by proteins the AAA and by N-terminal-regulatingATPase N-ethylmaleimide-sensitive motifs, which arefactor present (NSF) onin mostmammals SNAREs and [Sec18p10,11]. in After yeast, membrane which are fusion, the SNARErecruited complex by the adaptor is disassembled protein-soluble by the NSF-attachment AAA ATPase Nprotein-ethylmaleimide-sensitive α (α-SNAP) in mammals factor and (NSF) in mammalsSec17p in and yeast Sec18p [10,11]. in yeast, which are recruited by the adaptor protein-soluble NSF-attachment protein αIn( αmammalian-SNAP) in mammalscells, the Qa-SNARE and Sec17p Stx5 in yeast is an [ 10integral,11]. component of ER-derived COPII transportIn mammalian vesicles cells,and is the required Qa-SNARE for the Stx5docking is an an integrald fusion componentof these vesicles of ER-derived to assemble COPIIthe ERGIC transport vesicles[6,12] and by forming is required a SNARE for thecomplex docking with andGosR2 fusion (GS27, of membrin; these vesicles Qb-SNARE) to assemble or GosR1 the (GS28; ERGIC Qb), [6,12] Bet1 (Qc), and Ykt6 (R) or Sec22b (Ers24; R) (Figure 2) [13–19]. This process is well conserved in yeast, by forming a SNARE complex
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  • Essential Genes and Their Role in Autism Spectrum Disorder

    Essential Genes and Their Role in Autism Spectrum Disorder

    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Essential Genes And Their Role In Autism Spectrum Disorder Xiao Ji University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Bioinformatics Commons, and the Genetics Commons Recommended Citation Ji, Xiao, "Essential Genes And Their Role In Autism Spectrum Disorder" (2017). Publicly Accessible Penn Dissertations. 2369. https://repository.upenn.edu/edissertations/2369 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2369 For more information, please contact [email protected]. Essential Genes And Their Role In Autism Spectrum Disorder Abstract Essential genes (EGs) play central roles in fundamental cellular processes and are required for the survival of an organism. EGs are enriched for human disease genes and are under strong purifying selection. This intolerance to deleterious mutations, commonly observed haploinsufficiency and the importance of EGs in pre- and postnatal development suggests a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication and repetitive behavior. More and more genetic evidence points to a polygenic model of ASD and it is estimated that hundreds of genes contribute to ASD. The central question addressed in this dissertation is whether genes with a strong effect on survival and fitness (i.e. EGs) play a specific oler in ASD risk. I compiled a comprehensive catalog of 3,915 mammalian EGs by combining human orthologs of lethal genes in knockout mice and genes responsible for cell-based essentiality.