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Membrane-remodeling by SNX18 in endosomal transport and autophagy
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The intracellular space of eukaryotic cells is subdivided into functionally distinct membrane-enclosed organelles. Regulation of these intracellular membranes requires an intricate network of specialized lipids and proteins that maintain organellar integrity and mediate transport between organelles. Proteins of the sorting nexin (SNX) family are membrane-binding regulators of transport events within the endomembrane system. The endomembrane system includes organelles associated with endocytic, secretory and degradative processes in the cell. The aims of this thesis were to functionally characterize SNX18 and SNX33, members of the SNX9-subfamily of sorting nexins, and to elucidate the role of SNX18 in autophagy.

We demonstrated that all three proteins in the SNX9-family are capable of both membrane binding and remodeling, and interact with the membrane scission enzyme dynamin. We found that SNX18 localizes to endosomal structures in the endomembrane system, together with several identified factors previously described as regulators of endosomal transport. These results indicate that SNX18 mediates budding of membrane carriers in endosomal trafficking. In addition to this, knockdown of SNX18 in cultured cells was found to inhibit autophagy. Autophagy is a catabolic process by which cells degrade and recycle cellular components. It is a cellular response to various stress conditions such as oxidative stress, nutrient deprivation and infections. The components destined for degradation by autophagy are sequestered into a double-membrane structure called the autophagosome in which they are delivered to the lysosome. SNX18 interacts directly with proteins connected to autophagosome formation. Moreover, we demonstrated that the membrane-remodeling capability of SNX18 is a prerequisite for autophagosome formation.

Taken together, our results lead to the conclusions that SNX18 remodels cellular membranes during formation of carriers for endosomal transport and that it is a positive regulator of autophagy and autophagosome formation.

Place, publisher, year, pages
Department of Medical Biochemistry and Biophysics, Umeå University, 2012. 42 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1478
Keyword [en]
Sorting nexin, SNX9-family, SNX18, endosomal transport, autophagy
National Category
Cell and Molecular Biology
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-51999 (URN)978-91-7459-366-2 (ISBN)oai:DiVA.org:umu-51999 (OAI)diva2:492174 (DiVA)
Public defence
2012-02-29, KB3A9, KBC-huset, Linnaeus väg, Umeå Universitet, Umeå, 09:00 (English)
Opponent
Supervisors
Available from2012-02-08 Created:2012-02-07 Last updated:2012-02-08Bibliographically approved
List of papers
1. SNX18 is an SNX9 paralog that acts as a membrane tubulator in AP-1-positive endosomal trafficking.
Open this publication in new window or tab >>SNX18 is an SNX9 paralog that acts as a membrane tubulator in AP-1-positive endosomal trafficking.
2008 (English)In: Journal of Cell Science, ISSN 0021-9533, Vol. 121, no Pt 9, 1495-505Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-9591 (URN)18411244 (PubMedID)
Available from2008-04-29 Created:2008-04-29 Last updated:2012-02-08Bibliographically approved
2. The membrane-remodeling PX-BAR protein SNX18 is required for autophagy
Open this publication in new window or tab >>The membrane-remodeling PX-BAR protein SNX18 is required for autophagy
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Autophagy is a catabolic pathway targeting cytoplasmic material for lysosomal degradation,thereby protecting cells from accumulation of toxic components and enabling cells to survivescarce nutrient supplies. Macroautophagy is characterized by the sequestration of cytoplasmicmaterial into double-membrane vesicles, but the membrane remodeling events required forformation of autophagic vesicles are still not completely understood. However, the class IIIphosphatidylinositol 3-kinase (PI3K)/Vps34 complex and phosphatidylinositol-3-phosphate(PI3P) are of core importance to induction of autophagy. Since PX domain containingproteins are known to bind PI3P and other phosphoinositides and mediate membraneremodeling and trafficking events, we performed an imaging-based siRNA screen targetingPX domain proteins using formation of GFP-LC3 positive autophagosomes as a read-out.The PX-BAR protein SNX18 was found to strongly inhibit autophagosome formation. In linewith this, overexpression of SNX18 increased LC3 lipidation and GFP-LC3 spot formationand we demonstrate that membrane binding of SNX18 is required for efficientautophagosome formation. Moreover, SNX18 colocalizes and interacts with the autophagyassociatedproteins LC3 and TBK1. Our study identified the PX-BAR protein SNX18 to beinvolved in membrane events required for autophagosome formation.

National Category
Cell and Molecular Biology
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-51967 (URN)
Available from2012-02-07 Created:2012-02-06 Last updated:2012-02-08Bibliographically approved

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Håberg, Karin
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