SNX17 regulates Notch pathway and pancreas development through the retromer-dependent recycling of Jag1
© Yin et al. 2012
Received: 19 May 2012
Accepted: 28 June 2012
Published: 28 June 2012
Notch is one of the most important signaling pathways involved in cell fate determination. Activation of the Notch pathway requires the binding of a membrane-bound ligand to the Notch receptor in the adjacent cell which induces proteolytic cleavages and the activation of the receptor. A unique feature of the Notch signaling is that processes such as modification, endocytosis or recycling of the ligand have been reported to play critical roles during Notch signaling, however, the underlying molecular mechanism appears context-dependent and often controversial.
Here we identified SNX17 as a novel regulator of the Notch pathway. SNX17 is a sorting nexin family protein implicated in vesicular trafficking and we find it is specifically required in the ligand-expressing cells for Notch signaling. Mechanistically, SNX17 regulates the protein level of Jag1a on plasma membrane by binding to Jag1a and facilitating the retromer-dependent recycling of the ligand. In zebrafish, inhibition of this SNX17-mediated Notch signaling pathway results in defects in neurogenesis as well as pancreas development.
Our results reveal that SNX17, by acting as a cargo-specific adaptor, promotes the retromer dependent recycling of Jag1a and Notch signaling and this pathway is involved in cell fate determination during zebrafish neurogenesis and pancreas development.
In the canonical Notch pathway, membrane-bound ligand binds to the Notch (receptor) in the target cells and induces a series of proteolytic cleavages to release the Notch intracellular domain (NICD) from the plasma membrane. The NICD then translocates into the nucleus and activates the expression of Notch target genes [1, 2]. Studies during the past decade have revealed that ubiquitylation by the Neur or Mib family E3 ubiquitin ligases and subsequent endocytosis of Notch ligands are essential for the activation of this pathway [3, 4]. It has been proposed that endocytosis generates a pulling force on the Notch receptor and promotes the cleavage and the activation of the receptor. Otherwise, the internalized ligand can be recycled back to specific micro-domains on the plasma membrane conducive for Notch signaling. It has also been suggested that ligands can be activated by certain modifications during the recycling process [3–6]. However, the molecular nature of the modification remains elusive.
Sorting nexin (SNX) family proteins play diverse roles in processes such as endocytosis, intracellular protein sorting and endosomal signaling . The PX-BAR subfamily members of SNXs are able to induce membrane tubulation which is essential for the retromer-dependent cargo trafficking . The classic retromer is a multi-protein complex consists of a cargo-selective adaptor (Vps26-29-35) and a membrane-bound heterodimer of Vps5 (SNX1/2 in vertebrate) and Vps17 (SNX5/6 in vertebrate) . It regulates the retrograde trafficking of cargos such as the cation-independent mannose-6-phosphate receptor (CI-MPR) from endosome to the Golgi apparatus. Recently, retromer is found to play a critical role in Wnt signaling by promoting the recycling of Wntless [10–16]. Interestingly, it is SNX3 but not SNX1/2 or 5/6 that regulates the retromer-dependent recycling of Wntless [17, 18]. Another SNX family member, SNX27, can bind to the β2 adrenergic receptor and regulates the retromer-dependent endosome-to-plasma membrane trafficking of it . It remains to be investigated whether other SNXs play similar cargo specific regulatory roles in retromer-dependent trafficking.
We report here that SNX17 regulates Notch pathway and cell-fate determination during zebrafish neurogenesis and pancreas development. SNX17 binds to Jag1a and facilitates the retromer-dependent recycling of the ligand. In fact, direct inhibition of the retromer pathway also reduces Notch activation. Thus, our study revealed a novel SNX17/retromer pathway in the regulation of Notch signaling.
SNX17 regulates Notch signaling during zebrafish embryogenesis
SNX17 is required in the ligand-expressing cell for Notch signaling
SNX17 interacts with Jag1a through the FERM-like domain
SNX17 regulates the protein level of plasma membrane-associated Jag1a
The SNX17-stimulated accumulation of Jag1a on the plasma membrane could be a result of reduced internalization of the ligand, so we investigated whether SNX17 was required for the endocytosis of Jag1a. The endocytosis assay was performed as described . We found that knockdown or over-expression of SNX17 did not affect the endocytosis of Jag1a much (Figure 4B). The mild enhancement of endocytosis when SNX17 was over-expressed was most likely due to the elevated plasma membrane Jag1a protein level. We concluded that the SNX17 induced membrane accumulation of Jag1a cannot be a result of reduced endocytosis of Jag1a. We determined the subcellular distribution of Jag1a by immunofluorescence staining. As shown in Figure 4C, Jag1a was found at early endosomes, late endosomes and multivesicular bodies (MVB) but not Rab4-positive vesicles which are involved in the endosome-to-plasma membrane trafficking . When SNX17 was knocked-down, we found that Jag1a was internalized and transported to the Hrs-positive vesicle normally (bottom panel). These results further suggest that SNX17 regulates Jag1a through a mechanism independent of endocytosis.
SNX17 regulates the retromer-dependent recycling of Jag1a
It is well established that the endocytosis of ligand is pivotal for the activation of Notch pathway. One generally accepted model is that endocytosis generates a pulling force on the Notch receptor, which promotes the cleavage and the activation of the receptor. In polarized cells, the endocytosed ligand can be relocated to a position on the plasma membrane conducive to signaling. In this model, the transcytosed ligand is clustered or localized to micro-domains adjacent to Notch receptor where it can induce Notch activation efficiently. In this study, we identified vesicular trafficking protein SNX17 as a novel regulator of the Notch signaling both in vitro and in vivo. We show that SNX17 is not essential for the endocytosis of Jag1a but regulates the homeostasis of plasma membrane associated Jag1a. We propose that, by binding to SNX17, Jag1a escapes from the degradation and enters the recycling pathway which results in the accumulation of Jag1a on the plasma membrane.
Rab11-mediated recycling of ligand has been implicated in Notch activation in the drosophila. For example, it regulates the recycling of Delta in the sensory organ precursors [33, 34]. However, the requirement for recycling pathway in Delta signaling appears to be limited to specific cell types, since Rab11 is not essential for Delta signaling in other cells such as the germline cells or eye disc [35, 36]. We found that the Rab11 pathway is not involved in the recycling of Jag1a and down-regulation of Rab11 does not reduce the activity of Notch reporter. Unexpectedly, we found that the retromer pathway is required for Notch activation. A few previous studies reported that the retromer pathway is not involved in the regulation of Notch pathway in wing disc or the follicle epithelium in the drosophila [12, 13, 37]. This is contradictory to what we found here. However, context-dependent regulatory mechanisms are well known for Notch pathway, so it is possible that the retromer-mediated recycling of the ligand is required for Notch signaling in some cell types but not the others. Another possibility is that the role of endocytosis or recycling in Notch activation is ligand specific. For example, Mib-induced ubiquitylation is required for the endocytosis of Delta and subsequent Notch activation [28, 38]. Mib also ubiquitylates Jag1a and is required for the Jag1a-induced Notch activation, however, the endocytosis of Jag1a is largely Mib-independent. The exact function of Mib in Jag1a signaling remains to be characterized . It has been proposed that there are two types of ligand endocytosis: one is the constant endocytosis which regulates the homeostasis of ligand on the plasma membrane; the other is the signaling-specific endocytosis of the ligand. We found a large fraction of intracellular Jag1a at the Hrs vesicles, which usually enter the degradation pathway after fusion to lysosomes. This observation suggests that the rate of internalization and turnover of Jag1a is high in this cell. Under such circumstance, SNX17 could effectively regulates the protein level of plasma membrane associated Jag1a by binding to Jag1a and redirecting it from the degradation pathway to the retromer-dependent recycling pathway,
Vertebrate SNX1/2 and 5/6 are components of the retromer complex. Recent studies revealed that other SNX family proteins can play additional roles in retromer-dependent trafficking. For example, SNX3 functions as a cargo-specific adaptor for the retromer-dependent trafficking of Wntless [17, 18] while SNX27 can serve as an adaptor protein for the retromer -dependent endosome-to-plasma membrane trafficking of the β2 adrenergic receptor . We showed here that SNX17 is able to interact with Jag1a and regulate the retromer-dependent recycling of the ligand. It could be a general theme that SNX family proteins function as cargo-specific regulators in retromer-dependent vesicular trafficking. It will be interesting to test whether other SNX family members can function in similar manners and play regulatory roles in other cell signaling events.
We identified SNX17 as a tissue specific regulator of Notch pathway, and this SNX17-regulated Notch pathway is essential for inhibition of neurogenesis as well as cell fate determination in pancreas development. We revealed the molecular mechanism of SNX17: it does not affect the endocytosis of Jag1a; instead, it promotes the retromer-dependent recycling of the ligand which results in the accumulation of Jag1a protein on plasma membrane and enhanced Notch signaling.
Molecular cloning was performed according to standard protocols. The following constructs were used in this study: N-3Xflag-hSNX17 in pReceiver-M12, N-His-hSNX17 in pReceiver-M01, hSNX17-HA in PCR3.1,N-eGFP-hVps35 in pReceiver-M29, N-3Xflag-SNX17-PX, N-3Xflag-SNX17-FERM in pReceiver-M12, N-eGFP-Hrs in pReceiver-M29, GFP-Rab4 in pReceiver-M29,GFP-Rab5, GFP-Rab7 and GFP-Rab11in PCR3.1, hSNX17-GFP in PCR3.1, 8X CBF1 reporter (Notch luciferase reporter plasmid, a gift from Dr .M. M. Chiu). hJag1 and rNotch1 were cloned into the pBABE-Puro retroviral vector for making the stable cell lines. Jag1, Jag2, DeltaA, DeltaB, DeltaC and DeltaD were cloned in PCR3.1. dJagged1a-HA in pCS2+ was provided by Dr. M. Itoh. Full-length hSNX17 and the rNICD (a.a. 1751–2531) were cloned in the pCS2+ for making mRNAs in vitro for rescue experiments. All constructs were confirmed by DNA sequencing. Detailed information about the constructs is available upon request.
Zebrafish (the Longfin line) and embryos are maintained and staged as previously described . MOs were purchased from Gene-Tools (Corvallis, OR): MO1 (AGACCAACACTTTCTCACCAGCTTG, 3 ng), MO2 (GATGAAAGTGTGTGCTCACCTGTTC, 4 ng) and the standard control MO (CCTCTTACCTCAGTTACAATTTATA, 4 ng). MOs were injected at 1-cell stage. For rescue experiments, embryos were first injected with MO, 5–10 min later, embryos were injected second time with mRNA (100 pg of hSNX17 mRNA or 20 pg of rNICD mRNA). Injected embryos were fixed at the indicated stages and whole-mount in situ hybridization was performed as described . lfabp, insulin and trypsin were detected at day 3 embryos and huC assayed in 2–3 somite stage embryos. Research on animal was performed with the approval of the Guangzhou Institutes of Health ethical committee.
Notch luciferase reporter assay
293T and NIH3T3 cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% FBS (Gibco, CA). Cells were seeded in 24-well plate (5x104 cells/well) for 16 h then siRNAs (final concentration of 40 nM) were transfected with the DharmaFECT Transfection Reagent according to the manufacturer’s protocol (Thermo Fisher, MA). 24 h after transfection, cells were transfected again with the 8X CBF1 reporter plasmid (0.1 μg) and pRL-EF (10 ng). The firefly and renilla luciferase activities were determined with the Promega Dual luciferase assay system (Madison, WI) 48 h post transfection. The pRL-EF plasmid, which expresses renilla luciferase under the control of the EF-1 promoter, was used to normalize the transfection efficiency of the luciferase reporters. For the ligand stimulation assay, 24 h after siRNA treatment, cells were transfected with the ligand plasmid (1 μg), the 8X CBF1 reporter (0.1 μg) and the pRL-EF (10 ng) and luciferase activities were determined as describe above. For co-culture experiment, a 293 T cell line stably expressing human Jag1 and a NIH3T3 cell line stably expressing rNotch were established. In order to test the function of SNX17 in signal sending cells, 293 T-Jag1 cells were transfected with siRNAs as described before. NIH3T3-rNotch cells were seeded in 12-well plate (1x105cells/well) for 16 h then the 8X CBF1 reporter (0.4 μg) and pRL-EF (40 ng) were transfected into cells with the Lipofectamine 2000 reagent. 24 h after transfection, these transfected cells (5x104 each) were mixed and cultured for another 48 h and luciferase activities were assayed. For SNX17 knockdown in signal receiving cells, NIH3T3-rNotch cells were transfected with siRNAs to mouse SNX17 (40 nM) for 16 h then the 8X CBF1 reporter (0.4 μg) and pRL-EF (40 ng) were transfected with the Lipofectamine 2000 reagent. 24 h after transfection, these cells were co-cultured with 293 T-Jag1 cells and luciferase activity measured as describe above.
Total RNAs were extracted from 293 T cells or zebrafish embryos using the RNAqueous®-4PCR Kit (Ambion, CA). Reverse-transcription was performed using the ReverTra Ace (TOYOBO, Japan) and PCR reactions were performed with the SYBR®Premix Ex Taq™ Kit (TAKARA, Japan) on the ABI7300 Real-Time PCR System. The relative gene expression level was determined by the delta delta Ct method using the β-actin gene as the reference. The sequences of primers used were listed in Additional file 2: Table S1.
Co-IP and western blot
293 T cells in 100-mm dish were transfected with N3FSNX17 (6 μg) and dJag1a HA (3 μg). 36 h after transfection, cells were washed with PBS and lysed in 700 μl TNE buffer (50 mmol/L Tris–HCl, pH 7.5, 150 mmol/L NaCl, 1% Nonidet P-40, 1 mmol/L EDTA, 10 mM NaF and 1 mM Na3VO4) with the protease inhibitor cocktail (Roche) and PMSF for 30 min. Cell lysates were clarified by centrifugation and the Flag or HA resin (30 μl) was added into the supernatant and incubated for 4 h at 4 °C. The resin was washed with TNE buffer for 3 times and eluted by adding 80 μl of the Flag or HA peptide. The eluant was clarified, boiled in SDS-sample buffer and ready for western blot analysis. Western blot was performed according to the standard protocol with the following antibodies: HRP-conjugated mouse anti-GADPH mouse (1:3000, Abcam), mouse anti-TFR (1:1000, Invitrogen), anti-His mAb (27E8) (1:5000, CST), anti-Myc mAb (9E10) (1: 5000, Sigma), mouse anti-HA (1:1000, Beyotime Institute of Biotechnology), anti-Flag mAb (1:5000, Sigma), goat anti-mouse HRP (1:3000, Amersham Biosciences).
cells on cover slips were transfected with the indicated plasmids for 24 h then washed with PBS and fixed in MeOH at −20 °C for 5 min. Samples were permeablized in PBS containing 0.1% Triton X-100 for 10 min at R.T.. Fixed cells were then blocked in PBS/10% normal goat serum for 1 h, incubated in primary antibody for 1 h at R.T. and washed three times with PBS. Samples were incubated in goat anti- mouse antibody conjugated with TRITC secondary antibody for 1 h at R.T. and washed with PBS, counter-stained with DAPI, mounted on glass slides and ready for imaging. Fluorescence images were taken using the Leica TCS SP2 Spectral Confocal System and manipulated with Adobe Photoshop.
Surface biotinylation and endocytosis assay
293 T cells were first transfected with siRNAs for 24 h, then transfected again with dJag1a (3 μg) and His-SNX17 (6 μg) as indicated for 48 h. For surface biotinylation assay, plasma membrane proteins were labeled with biotin and isolated with the Pierce Cell Surface Protein Isolation Kit. For endocytosis assay, the biotinylation buffer was removed and cells were incubated at 37 °C for 60 min. The remaining cell-surface biotin was stripped by three 25-min incubations with stripping buffer (50 mM MesNa, 50 mM Tris pH 8.3, 100 mM NaCl, 1 mM EDTA, 0.2% BSA) on ice. Cells were then lysed and the biotinylated proteins in the lysate were pulled-down with streptavidin-agarose. The protein level of Jag1a and was then determined by western blot.
We thank M. Itoh, M.M. Chiu, G. Weinmaster, J. Hald, Z. Li and D. Yao for reagents and other members of our lab for technical support. This work was supported by grants from the “Strategic Priority Research Program” of the Chinese Academy of Sciences (XDA01020401, XDA01020307), Ministry of Science and Technology 973 program (2009CB941102) and CAS 100-talent project (X.S.).
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