SNX9 – a prelude to vesicle release

Lundmark, Richard

doi:10.1242/jcs.037135

Cited by 86 publications

(110 citation statements)

References 66 publications

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“…The most pronounced effects were observed upon suppression of SNX9, a protein with an established role in endocytosis including that of the EGFR (Lundmark and Carlsson, 2009), and SNX5, classically considered a component of the SNX-BAR-retromer that regulates early-to-late transition endosome-to-TGN retrograde transport Wassmer et al, 2009;van Weering et al, 2012a). More recently, however, through an association with PIPKIci5, SNX5 has been shown to regulate EGFR sorting into intraluminal vesicles of the late endosome/multivesicular body in a manner that is independent of the retromer components VPS26 and VPS35 (Sun et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Based on these criteria, of the 30 SNXs tested only five gave an EGFR phenotype. Proving the validity of the screen, the most pronounced effects were observed following suppression of SNX9, a protein with an established role in endocytosis (Lundmark and Carlsson, 2009), and SNX5, which through an association with the type Ic phosphatidylinositol 4-phosphate 5-kinase i5 (PIPKIci5), is required for EGFR sorting into intraluminal vesicles of the late endosome/multivesicular body, a prerequisite for lysosomal-mediated degradation (Sun et al, 2013). The remaining SNXs were SNX3, SNX15 and SNX21.…”

Section: Sorting Nexin Loss-of-function Screen Reveals a Role For Snxmentioning

confidence: 99%

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SNX15 links clathrin endocytosis to the PtdIns(3)P early endosome independent of the APPL1 endosome

Danson¹,

Brown²,

Hemmings³

et al. 2013

Journal of Cell Science

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SummarySorting nexins (SNXs) are key regulators of the endosomal network. In designing an RNAi-mediated loss-of-function screen, we establish that of 30 human SNXs only SNX3, SNX5, SNX9, SNX15 and SNX21 appear to regulate EGF receptor degradative sorting. Suppression of SNX15 results in a delay in receptor degradation arising from a defect in movement of newly internalised EGF-receptorlabelled vesicles into early endosomes. Besides a phosphatidylinositol 3-phosphate-and PX-domain-dependent association to early endosomes, SNX15 also associates with clathrin-coated pits and clathrin-coated vesicles by direct binding to clathrin through a noncanonical clathrin-binding box. From live-cell imaging, it was identified that the activated EGF receptor enters distinct sub-populations of SNX15-and APPL1-labelled peripheral endocytic vesicles, which do not undergo heterotypic fusion. The SNX15-decorated receptorcontaining sub-population does, however, undergo direct fusion with the Rab5-labelled early endosome. Our data are consistent with a model in which the EGF receptor enters the early endosome following clathrin-mediated endocytosis through at least two parallel pathways: maturation through an APPL1-intermediate compartment and an alternative more direct fusion between SNX15-decorated endocytic vesicles and the Rab5-positive early endosome.

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Section: Discussionmentioning

confidence: 99%

Section: Sorting Nexin Loss-of-function Screen Reveals a Role For Snxmentioning

confidence: 99%

SNX15 links clathrin endocytosis to the PtdIns(3)P early endosome independent of the APPL1 endosome

Danson¹,

Brown²,

Hemmings³

et al. 2013

Journal of Cell Science

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“…7C,D) only partially rescued the endocytic defects caused by either SNX18 or SNX9 depletion, suggesting that full-length SNX9 or SNX18 is required for complete rescue. This is conceivable considering that SNX18 and SNX9 are composed of four functional domains (SH3, LC, PX and BAR) that are known to bind a variety of proteins to regulate various steps of clathrin-mediated endocytosis (Lundmark and Carlsson, 2009;Shin et al, 2008).…”

Section: Snx18 Can Replace the Function Of Snx9 During Clathrinmediatmentioning

confidence: 99%

“…and clathrin also bind to the low-complexity (LC) region of SNX9 in a cooperative manner (Lundmark and Carlsson, 2003;Lundmark and Carlsson, 2009;Shin et al, 2008). The SNX family contains two proteins that are closely related to SNX9: SNX18 and SNX33.…”

Section: Introductionmentioning

confidence: 99%

SNX18 shares a redundant role with SNX9 and modulates endocytic trafficking at the plasma membrane

Park

Kim

Lee

et al. 2010

Journal of Cell Science

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SNX18 and SNX9 are members of a subfamily of SNX (sorting nexin) proteins with the same domain structure. Although a recent report showed that SNX18 and SNX9 localize differently in cells and appear to function in different trafficking pathways, concrete evidence regarding whether they act together or separately in intracellular trafficking is still lacking. Here, we show that SNX18 has a similar role to SNX9 in endocytic trafficking at the plasma membrane, rather than having a distinct role. SNX18 and SNX9 are expressed together in most cell lines, but to a different extent. Like SNX9, SNX18 interacts with dynamin and stimulates the basal GTPase activity of dynamin. It also interacts with neuronal Wiskott-Aldrich syndrome protein (N-WASP) and synaptojanin, as does SNX9. SNX18 and SNX9 can form a heterodimer and colocalize in tubular membrane structures. Depletion of SNX18 by small hairpin RNA inhibited transferrin uptake. SNX18 successfully compensates for SNX9 deficiency during clathrin-mediated endocytosis and vice versa. Total internal reflection fluorescence microscopy in living cells shows that a transient burst of SNX18 recruitment to clathrin-coated pits coincides spatiotemporally with a burst of dynamin and SNX9. Taken together, our results suggest that SNX18 functions with SNX9 in multiple pathways of endocytosis at the plasma membrane and that they are functionally redundant.

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“…Once phosphorylated by TβRI, they most often form a heterotrimer consisting of 2 molecules of either SMAD2 or SMAD3 complexed with SMAD4 prior to undergoing nuclear translocation, where they function as comodulators of gene expression. Recently, we have extended this model and provide evidence that sorting nexin 9 (SNX9), a member of the PX/BAR subfamily of intracellular trafficking proteins (19)(20)(21)(22)(23), has an obligate role in mediating phosphorylated SMAD3 (pSMAD3) nuclear import following ligand treatment (24).…”

Section: Introductionmentioning

confidence: 99%

Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling

Kang¹,

Jung²,

Yin³

et al. 2017

Journal of Clinical Investigation

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ResultsA TAT-SNX9 peptide specifically blocks pSMAD3 nuclear import and profibrotic TGF-β signaling. We previously determined that SNX9 has an obligate role in mediating profibrotic TGF-β signaling dependent upon SMAD3 (24). In order to investigate colony formation, and cell migration; and (b) fibrotic changes associated with the bleomycin (BLM) and adenoviral models of lung fibrosis. Moreover, a 3-amino acid point mutant of the TAT-SNX9 peptide unable to bind pSMAD3 was ineffective in analogous in vitro and in vivo assays. Lysates from AKR-2B cells untreated (-) or stimulated (+) for 45 minutes with 5 ng/ml TGF-β were incubated with GST beads or the indicated fusion proteins immobilized on GST beads. Bound proteins were eluted and assessed by Western blot analysis for pSMAD3 or pSMAD2. Cell lysate reflects signal obtained from 10 μg total protein; the slower migrating band in the pSMAD3 lane is a nonspecific protein (right, representative of 3 separate experiments). (B) AKR-2B cells were transduced for 90 minutes with the indicated concentration of TAT peptide. Following washing and 1 hour TGF-β (5 ng/ml) treatment, nuclear fractions were isolated and assessed by Western blot analysis for pSMAD2, pSMAD3, or histone deacetylase 1 (HDAC) (left, representative of 3 separate experiments). Quantitation of nuclear pSMADs was performed with ImageJ software (NIH) and represents the mean ± SEM of 3 experiments (right). (C) Left panels: AKR-2B cells were incubated with vehicle (top panels) or transduced (bottom panels) as in B with TAT-SH3 or TAT-LC (1.8 μM). Following treatment with or without TGF-β (5 ng/ml) for 1 hour, immunofluorescence for SMAD3 or the HA-tagged TAT peptide was performed as described in Methods and nuclei were stained with DAPI. Upper and lower panels show 2 distinct microscopic fields for each condition. Original magnification in C: ×100. Right: quantitation of nuclear SMAD3 from 30 cells in each of 3 experiments. *P < 0.05; **P < 0.005; ***P < 0.0005, 1-way ANOVA followed by Dunnett's multiple comparisons test. The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 5 4 3 jci.orgVolume 127 Number 7 July 2017 sion of this fragment could act in trans as a dominant inhibitor of pSMAD3 nuclear uptake. To address this issue, constructs were prepared expressing either the SNX9 SH3 or LC domains fused to the cell-penetrating TAT peptide from HIV (39). Subsequent to TAT peptide transduction, cultures were treated with TGF-β and nuclear accumulation of pSMAD2 or pSMAD3 determined. As shown in Figure 1B and Supplemental Figure 2, while the TAT-SH3 peptide inhibited nuclear import of pSMAD3 in a dose-dependent manner and increased cytoplasmic pSMAD3, it had no effect on pSMAD2. Furthermore, consistent with the inability of the LC domain to bind receptorregulated SMADs (R-SMADs) ( Figure 1A), it was similarly ineffective in modulating nuclear translocation ( Figure 1B). These biochemical findings were independently confirmed using immunofluorescence ( Figure 1C and Supplemental Figure 3). While t...

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SNX9 – a prelude to vesicle release

Cited by 86 publications

References 66 publications

SNX15 links clathrin endocytosis to the PtdIns(3)P early endosome independent of the APPL1 endosome

SNX15 links clathrin endocytosis to the PtdIns(3)P early endosome independent of the APPL1 endosome

SNX18 shares a redundant role with SNX9 and modulates endocytic trafficking at the plasma membrane

Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-β signaling

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