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This Is the End: Regulation of Rab7 Nucleotide Binding in Endolysosomal Trafficking and Autophagy.

ABSTRACT: Rab7 - or in yeast, Ypt7p - governs membrane trafficking in the late endocytic and autophagic pathways. Rab7 also regulates mitochondrion-lysosome contacts, the sites of mitochondrial fission. Like all Rab GTPases, Rab7 cycles between an "active" GTP-bound form that binds downstream effectors - e.g., the HOPS and retromer complexes and the dynactin-binding Rab-interacting lysosomal protein (RILP) - and an "inactive" GDP-bound form that cannot bind effectors. Accessory proteins regulate the nucleotide binding state of Rab7: guanine nucleotide exchange factors (GEFs) stimulate exchange of bound GDP for GTP, resulting in Rab7 activation, whereas GTPase activating proteins (GAPs) boost Rab7's GTP hydrolysis activity, thereby inactivating Rab7. This review will discuss the GEF and GAPs that control Rab7 nucleotide binding, and thus regulate Rab7's activity in endolysosomal trafficking and autophagy. It will also consider how bacterial pathogens manipulate Rab7 nucleotide binding to support intracellular invasion and immune evasion.

SUBMITTER: Stroupe C

PROVIDER: S-EPMC6176412 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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This Is the End: Regulation of Rab7 Nucleotide Binding in Endolysosomal Trafficking and Autophagy.

Stroupe Christopher C

Frontiers in cell and developmental biology 20181002

Rab7 - or in yeast, Ypt7p - governs membrane trafficking in the late endocytic and autophagic pathways. Rab7 also regulates mitochondrion-lysosome contacts, the sites of mitochondrial fission. Like all Rab GTPases, Rab7 cycles between an "active" GTP-bound form that binds downstream effectors - e.g., the HOPS and retromer complexes and the dynactin-binding Rab-interacting lysosomal protein (RILP) - and an "inactive" GDP-bound form that cannot bind effectors. Accessory proteins regulate the nucle ...[more]

PMID: 30333976

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Project description:Background and purposeDysfunction of the endolysosomal system can cause cell death. A key molecule for controlling the endolysosomal trafficking activities is the N-ethylmaleimide-sensitive factor (NSF) ATPase. This study investigates the cascades of NSF ATPase inactivation events, endolysosomal damage, cathepsin release, and neuronal death after focal brain ischemia.MethodsA total of 62 rats were used in this study. They were subjected to sham surgery or 2 h of focal brain ischemia followed by 1, 4, and 24 h of reperfusion. Confocal microscopy and Western blot analysis were utilized to analyze the levels, redistribution, and co-localization of key proteins of the Golgi apparatus, late endosomes, endolysosomes, and lysosomes. Light and electron microscopy were used to examine the histopathology, protein aggregation, and endolysosomal ultrastructures.ResultsTwo hours of focal brain ischemia in rats led to acute neuronal death at the striatal core in 4 h and a slower type of neuronal death in the neocortical area during 1-24 h reperfusion periods. Confocal microscopy showed that NSF immunoreactivity was irreversibly and selectively depleted from most, if not all, post-ischemic penumbral neurons. Western blot analysis further demonstrated that NSF depletion from brain sections was due to its deposition into dense inactive aggregates that could not be recognized by the NSF antibody. Commitantly, the Golgi apparatus was completely fragmented and cathepsin B (CTSB)-containing endolysosomal structures, as well as p62/SQSTM1- and EEA1-immunopositive structures were massively accumulated in the post-ischemic penumbral neurons. Ultimately, CTSB was released into the cytoplasm and extracellular space, causing stroke brain injury.ConclusionStroke Inactivates NSF, resulting in disruption of the reforming of functional endolysosomal compartments, blockade of the endocytic and autophagic pathways, a large scale of CTSB release into the cytoplasm and extracellular space, and stroke brain injury in the rat model.

Project description:Endocytosis and endolysosomal trafficking are essential for almost all aspects of physiological functions of eukaryotic cells. As our understanding on these membrane trafficking events are mostly from studies in yeast and cultured mammalian cells, one challenge is to systematically evaluate the findings from these cell-based studies in multicellular organisms under physiological settings. One potentially valuable in vivo system to address this challenge is the vitellogenic oocyte in Drosophila, which undergoes extensive endocytosis by Yolkless (Yl), a low-density lipoprotein receptor (LDLR), to uptake extracellular lipoproteins into oocytes and package them into a specialized lysosome, the yolk granule, for storage and usage during later development. However, by now there is still a lack of sufficient understanding on the molecular and cellular processes that control yolk granule biogenesis. Here, by creating genome-tagging lines for Yl receptor and analyzing its distribution in vitellogenic oocytes, we observed a close association of different endosomal structures with distinct phosphoinositides and actin cytoskeleton dynamics. We further showed that Rab5 and Rab11, but surprisingly not Rab4 and Rab7, are essential for yolk granules biogenesis. Instead, we uncovered evidence for a potential role of Rab7 in actin regulation and observed a notable overlap of Rab4 and Rab7, two Rab GTPases that have long been proposed to have distinct spatial distribution and functional roles during endolysosomal trafficking. Through a small-scale RNA interference (RNAi) screen on a set of reported Rab5 effectors, we showed that yolk granule biogenesis largely follows the canonical endolysosomal trafficking and maturation processes. Further, the data suggest that the RAVE/V-ATPase complexes function upstream of or in parallel with Rab7, and are involved in earlier stages of endosomal trafficking events. Together, our study provides s novel insights into endolysosomal pathways and establishes vitellogenic oocyte in Drosophila as an excellent in vivo model for dissecting the highly complex membrane trafficking events in metazoan.

Dataset Information

This Is the End: Regulation of Rab7 Nucleotide Binding in Endolysosomal Trafficking and Autophagy.

Publications

This Is the End: Regulation of Rab7 Nucleotide Binding in Endolysosomal Trafficking and Autophagy.

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