Mecanismos reguladores del tráfico en la interfaz retículo endoplasmático/Golgi
[EN] The secretory pathway transports proteins and lipids from the Endoplasmatic Reticulum (ER) to the plasma membrane and extracellular millieu, or to the membrane-bound compartments of the endosomal-lysosomal system. The first step of this pathway is the incorporation to vesicles bound for the Gol...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/353784 |
| Acceso en línea: | http://hdl.handle.net/10261/353784 |
| Access Level: | acceso abierto |
| Palabra clave: | Retículo endoplasmático Transporte de proteínas Aparato de Golgi http://metadata.un.org/sdg/3 Ensure healthy lives and promote well-being for all at all ages |
| Sumario: | [EN] The secretory pathway transports proteins and lipids from the Endoplasmatic Reticulum (ER) to the plasma membrane and extracellular millieu, or to the membrane-bound compartments of the endosomal-lysosomal system. The first step of this pathway is the incorporation to vesicles bound for the Golgi of the proteins synthetized by the ER-associated ribosomes, once these have been properly folded and the necessary posttranslational modifications added [1, 2]. In their journey throughout the Golgi cisternae, these proteins, collectively known as cargo, are subjected to further modifications in their N- and O-glycosilation patterns [3, 4]. Finally, cargo arrives to the Trans-Golgi Network (TGN), where is sorted and concentrated into specialized domains, and subsequently exported by membrane carriers bound for the PM or the endosomal-lysosomal system [5]. Transit through the different pathways of intracellular trafficking is regulated at the molecular level by several mechanisms that, on the one hand, secure that cargo reaches its destination, and on the other, maintain the identity of the different compartments that constitute the endomembrane system [6, 7]. Small GTPases of the Rab and Arf families play a fundamental role as molecular switches, recruiting peripheral membrane proteins to the specific location where they are needed [8]. The loading/hydrolysis cycle of a GTPase is governed by a set of regulators, the most crucial of whom are the Guanine nucleotide Exchange Factors (GEFs) and the GTPase activating Proteins (GAPs), which are responsible for the loading of GTP and its hydrolysis, respectively[11, 12]. The main focus of this doctoral thesis is the study of certain regulatory aspects of ER to early Golgi trafficking. This process begins with the activation of the Sar1 GTPase by its cognate GEF, Sec12 [13, 14]. The GTP-bound form of Sar1 gets anchored to the ER membrane and starts the recruitment of the Coat Protein Complex II (COPII) subunits, firstly, the inner layer composed of Sec23-Sec24 subunits [15] . One of the main roles of these subunits is to serve as adaptors for the soluble cargo receptors and other transmembrane proteins exported from the ER [16]. The outer layer of the COPII coat (Sec13-Sec31) contributes to budding of transport vesicles by inducing ER membrane deformation[17]. Those domains of the ER specialized in COPII biogenesis and cargo export are known as ER Exit Sites (ERES) [18, 19]. Vesicles are transported by motor proteins along the cytoskeleton to their destination, the early Golgi cisternae [20]. The step preceding membrane fusion is the capture or tethering of vesicles, a process mediated by compartment-specific tethering factors that behave as a selectivity filter that ensures the fusion of donor vesicles with the correct target membrane [21, 22]. Some tethers found in early Golgi cisternae exhibit a characteristic coiled-coil structure: p115/Uso1, GM130/Bug1 or CASP/Coy1. These coiled-coil tethers are known as golgins, and they are recruited to membranes by activated Rab GTPases [23]. Once the vesicle is close enough to the acceptor membrane, a complex of four transmembrane proteins named SNAREs (Soluble NSF Attachment protein REceptors) is established [24]. The parallel pairing of the 4 α-helical SNARE motifs creates a thermodynamically favorable zippering which brings together the two apposed lipid bilayers [25-27]. |
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