Sven Carlsson - Professor

SNX9-protein family: Structure and function in intracellular trafficking and autophagy

We have identified an intracellular protein, called sorting nexin 9 (SNX9), that play a crucial role for the release of transport vesicles formed at the plasma membrane. Studies of the biochemical properties of recombinant and endogenous SNX9 have brought forward this protein as a recruiter of dynamin to the neck of clathrin-coated vesicles. Members of the dynamin family of large GTPases are involved in membrane fission events that take place during intracellular trafficking of proteins and lipids. Dynamin oligomerization at the base of the bud stimulates the hydrolysis of GTP, which leads to constriction through a conformational change and deformation of the membrane. This activity needs to be restricted to membrane areas that possess high curvature like the vesicular neck.

SNX9 belongs to a subfamily of sorting nexins that in addition to a phosphoinositide-specific PX (phox) domain has a membrane-sculpting BAR (Bin/amphiphysin/Rvs) domain. The domain structure of SNX9 is well adapted to fit into the complex network of interacting proteins that come together to generate a clathrin coated vesicle at the plasma membrane. An amino terminal SH3 (src homology 3) domain binds to the proline-rich region of dynamin. This interaction is strong enough to form an endogenous complex between SNX9 and dynamin already in the cytosol. To link into the vesicle budding network, SNX9 has an unstructured region (LC region) with motifs for binding to the core components AP-2 and clathrin. The PX-BAR unit of SNX9 targets the SNX9-dynamin complex to the plasma membrane. In combination with the interactions with AP-2 and clathrin, the membrane-binding properties of SNX9 are anticipated to precisely target SNX9 to the highly curved neck of the clathrin coated pit.

We have reported the crystal structures of the functional membrane remodeling PX-BAR unit of SNX9 and have shown that it efficiently tubulates lipid membranes in vivo and in vitro. Elucidation of the protein superdomain structure, together with mutational analysis and biochemical and cell biological experiments, have demonstrated how the SNX9 PX and BAR domains work in concert in targeting and tubulation of phosphoinositide-containing membranes. These studies provide insights into the SNX9-induced membrane-modulation mechanism.

SNX9, SNX18, and SNX33 constitute a separate sub-family of PX-BAR-containing sorting nexin proteins. On-going studies aim to understand the specific roles of SNX18 and SNX33. Results have shown that SNX18 is a positive regulator of autophagosome biogenesis. SNX18 interacts with autophagy factors ATG16L1 and LC3, and functions downstream of ATG14 and the class III PtdIns3K complex in autophagosome formation. SNX18 facilitates recruitment of ATG16L1 to perinuclear recycling endosomes, and its overexpression leads to tubulation of ATG16L1- and LC3-positive membranes.  We propose that SNX18 promotes LC3 lipidation and tubulation of recycling endosomes to provide membrane for phagophore expansion.


Selected recent publications

Holland P, Knævelsrud H, Søreng K, Mathai BJ, Lystad AH, Pankiv S, Bjørndal GT, Schultz SW, Lobert VH, Chan RB, Zhou B, Liestøl K, Carlsson SR, Melia TJ, Di Paolo G, Simonsen A. HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels.
Nature Communications 7:13889 (1-13). 2016.

Klionsky DJ et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Autophagy, 12: 1-222. 2016

Carlsson, S.R. and Simonsen A. Membrane dynamics in autophagosome biogenesis.
Journal of Cell Science, 128: 193-205. 2015.

Knævelsrud, H., Carlsson, S.R., and Simonsen, A. SNX18 tubulates recycling endosomes for autophagosome biogenesis.
Autophagy, 9: 1639-1641. 2013

Knævelsrud, H., Søreng, K., Raiborg, C, Håberg, K., Rasmuson, F., Brech, A., Liestøl, K., Rusten, T.E., Stenmark, H., Neufeld, T.P., Carlsson, S.R., Simonsen, A. Membrane remodeling by the PX-BAR protein SNX18 promotes autophagosome formation.
Journal of Cell Biology, 202, 331-49. 2013.

van Weering, J.R., Sessions, R.B., Traer, C.J., Kloer, D.P., Bhatia, V.K., Stamou, D., Carlsson, S.R., Hurley, J.H., Cullen, P.J. Molecular basis for SNX-BAR-mediated assembly of distinct endosomal sorting tubules.
EMBO Journal, 31, 4466-80. 2012.

Lundmark, R. & Carlsson, S.R. Driving membrane curvature in clathrin-dependent and clathrin-independent endocytosis.
Seminars in Cell and Developmental Biology, 21, 363-370. 2010

Lundmark, R. & Carlsson, S.R. SNX9: a prelude to vesicle release.
Journal of Cell Science, 122, 5-11. 2009

Håberg K., Lundmark R., and Carlsson, S.R. SNX18 is an SNX9 paralog that acts as a membrane tubulator in AP-1-positive endosomal trafficking.
Journal of Cell Science, 121, 1495-1505. 2008.

Pylypenko, O., Lundmark, R., Rasmuson, E., Carlsson, S.R., and Rak, A. The PX-BAR membrane-remodeling unit of sorting nexin 9.
EMBO Journal, 26, 4788-4800. 2007.

Lundmark, R. and Carlsson, S.R. Regulated membrane recruitment of dynamin-2 mediated by sorting nexin 9.
Journal of Biological Chemistry, 279, 42694-42702. 2004.

Lundmark, R. and Carlsson, S.R. Sorting nexin 9 participates in clathrin-mediated endocytosis through interactions with the core components.
Journal of Biological Chemistry, 278, 46772-46781. 2003.

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Sven Carlsson

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Umeå University
Medical Biochemistry and Biophysics
SE-901 87 Umeå, SWEDEN 

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