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      The integration of autophagy and cellular trafficking pathways via RAB GAPs

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Macroautophagy is a conserved degradative pathway in which a double-membrane compartment sequesters cytoplasmic cargo and delivers the contents to lysosomes for degradation. Efficient formation and maturation of autophagic vesicles, so-called phagophores that are precursors to autophagosomes, and their subsequent trafficking to lysosomes relies on the activity of small RAB GTPases, which are essential factors of cellular vesicle transport systems. The activity of RAB GTPases is coordinated by upstream factors, which include guanine nucleotide exchange factors (RAB GEFs) and RAB GTPase activating proteins (RAB GAPs). A role in macroautophagy regulation for different TRE2-BUB2-CDC16 (TBC) domain-containing RAB GAPs has been established. Recently, however, a positive modulation of macroautophagy has also been demonstrated for the TBC domain-free RAB3GAP1/2, adding to the family of RAB GAPs that coordinate macroautophagy and additional cellular trafficking pathways.

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          Functional dissection of Rab GTPases involved in primary cilium formation

          Shin-ichiro Yoshimura, Johannes Egerer, Evelyn Fuchs … (2007)
          Primary cilia are sensory structures involved in morphogen signalling during development, liquid flow in the kidney, mechanosensation, sight, and smell (Badano, J.L., N. Mitsuma, P.L. Beales, and N. Katsanis. 2006. Annu. Rev. Genomics Hum. Genet. 7:125–148; Singla, V., and J.F. Reiter. 2006. Science. 313:629–633.). Mutations that affect primary cilia are responsible for several diseases, including neural tube defects, polycystic kidney disease, retinal degeneration, and cancers (Badano et al., 2006; Singla and Reiter, 2006). Primary cilia formation and function requires tight integration of the microtubule cytoskeleton with membrane trafficking (Singla and Reiter, 2006), and this is poorly understood. We show that the Rab GTPase membrane trafficking regulators Rab8a, -17, and -23, and their cognate GTPase-activating proteins (GAPs), XM_037557, TBC1D7, and EVI5like, are involved in primary cilia formation. However, other human Rabs and GAPs are not. Additionally, Rab8a specifically interacts with cenexin/ODF2, a basal body and microtubule binding protein required for cilium biogenesis (Ishikawa, H., A. Kubo, S. Tsukita, and S. Tsukita. 2005. Nat. Cell Biol. 7:517–524), and is the sole Rab enriched at primary cilia. These findings provide a basis for understanding how specific membrane trafficking pathways cooperate with the microtubule cytoskeleton to give rise to the primary cilia.
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            Neutral lipid stores and lipase PNPLA5 contribute to autophagosome biogenesis.

            E. Castillo-Montiel, Horst Robenek, Nicolas Dupont … (2014)
            Autophagy is a fundamental cell biological process whereby eukaryotic cells form membranes in the cytoplasm to sequester diverse intracellular targets. Although significant progress has been made in understanding the origins of autophagosomal organelles, the source of lipids that support autophagic membrane formation remain an important open question. Here we show that lipid droplets as cellular stores of neutral lipids including triglycerides contribute to autophagic initiation. Lipid droplets, as previously shown, were consumed upon induction of autophagy by starvation. However, inhibition of autophagic maturation by blocking acidification or using dominant negative Atg4(C74A) that prohibits autophagosomal closure did not prevent disappearance of lipid droplets. Thus, lipid droplets continued to be utilized upon induction of autophagy, but not as autophagic substrates in a process referred to as lipophagy. We considered an alternative model whereby lipid droplets were consumed not as a part of lipophagy, but as a potential contributing source to the biogenesis of lipid precursors for nascent autophagosomes. We carried out a screen for a potential link between triglyceride mobilization and autophagy and identified a neutral lipase, PNPLA5, as being required for efficient autophagy. PNPLA5, which localized to lipid droplets, was needed for optimal initiation of autophagy. PNPLA5 was required for autophagy of diverse substrates, including degradation of autophagic adaptors, bulk proteolysis, mitochondrial quantity control, and microbial clearance. Lipid droplets contribute to autophagic capacity by enhancing it in a process dependent on PNPLA5. Thus, neutral lipid stores are mobilized during autophagy to support autophagic membrane formation. Copyright © 2014 Elsevier Ltd. All rights reserved.
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              Trs85 directs a Ypt1 GEF, TRAPPIII, to the phagophore to promote autophagy.

              D J Klionsky, C Bartholomew, Ju-Sui Huang … (2010)
              Macroautophagy (hereafter autophagy) is a ubiquitous process in eukaryotic cells that is integrally involved in various aspects of cellular and organismal physiology. The morphological hallmark of autophagy is the formation of double-membrane cytosolic vesicles, autophagosomes, which sequester cytoplasmic cargo and deliver it to the lysosome or vacuole. Thus, autophagy involves dynamic membrane mobilization, yet the source of the lipid that forms the autophagosomes and the mechanism of membrane delivery are poorly characterized. The TRAPP complexes are multimeric guanine nucleotide exchange factors (GEFs) that activate the Rab GTPase Ypt1, which is required for secretion. Here we describe another form of this complex (TRAPPIII) that acts as an autophagy-specific GEF for Ypt1. The Trs85 subunit of the TRAPPIII complex directs this Ypt1 GEF to the phagophore assembly site (PAS) that is involved in autophagosome formation. Consistent with the observation that a Ypt1 GEF is directed to the PAS, we find that Ypt1 is essential for autophagy. This is an example of a Rab GEF that is specifically targeted for canonical autophagosome formation.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Autophagy
                Journal ID (iso-abbrev): Autophagy
                Journal ID (pmc): KAUP
                Title: Autophagy
                Publisher: Taylor & Francis
                ISSN (Print): 1554-8627
                ISSN (Electronic): 1554-8635
                Publication date Collection: December 2015
                Publication date (Electronic): 13 November 2015
                Publication date PMC-release: 13 November 2015
                Volume: 11
                Issue: 12
                Pages: 2393-2397
                Affiliations
                [1 ]Institute for Pathobiochemistry; University Medical Center of the Johannes Gutenberg University ; Mainz, Germany
                [2 ]Buchmann Institute for Molecular Life Sciences; Goethe University Frankfurt ; Frankfurt am Main, Germany
                Author notes
                [* ]Correspondence to: Christian Behl; Email: cbehl@ 123456uni-mainz.de
                Article
                Publisher ID: 1110668
                DOI: 10.1080/15548627.2015.1110668
                PMC ID: 4835203
                PubMed ID: 26565612
                SO-VID: 3c1d9577-51b7-4253-bee9-d063802be585
                Copyright © © 2015 The Author(s). Published with license by Taylor & Francis Group, LLC
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                History
                Date received : 27 July 2015
                Date revision received : 14 October 2015
                Date accepted : 14 October 2015
                Page count
                Figures: 1, Tables: 1, References: 50, Pages: 5
                Categories
                Subject: View and Commentary

                ScienceOpen disciplines: Molecular biology
                Keywords: autophagosome formation,autophagy,rab gap,rab gtpase,rab3gap,vesicle trafficking
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: autophagosome formation, autophagy, rab gap, rab gtpase, rab3gap, vesicle trafficking

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