- Open Access
The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway
© Sullivan et al. 2016
Received: 6 May 2016
Accepted: 7 May 2016
Published: 18 May 2016
Hexanucleotide repeat expansion in the C9orf72 gene is a leading cause of frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS). Reduced expression of C9orf72 has been proposed as a possible disease mechanism. However, the cellular function of C9orf72 remains to be characterized. Here we report the identification of two binding partners of C9orf72: SMCR8 and WDR41. We show that WDR41 interacts with the C9orf72/SMCR8 heterodimer and WDR41 is tightly associated with the Golgi complex. We further demonstrate that C9orf72/SMCR8/WDR41 associates with the FIP200/Ulk1 complex, which is essential for autophagy initiation. C9orf72 deficient mice, generated using the CRISPR/Cas9 system, show severe inflammation in multiple organs, including lymph node, spleen and liver. Lymph node enlargement and severe splenomegaly are accompanied with macrophage infiltration. Increased levels of autophagy and lysosomal proteins and autophagy defects were detected in both the spleen and liver of C9orf72 deficient mice, supporting an in vivo role of C9orf72 in regulating the autophagy/lysosome pathway. In summary, our study elucidates potential physiological functions of C9orf72 and disease mechanisms of ALS/FTLD.
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two devastating neurodegenerative diseases, which due to overlaps in clinical presentations, pathological features, and genetic causes, are considered two manifestations of a continuous disease spectrum [1, 7, 15, 29, 30, 49].
Many novel genes have been recently associated with ALS/FTLD [29, 37]. Among these, hexanucleotide repeat expansion in the C9orf72 gene has been shown to be the main cause of ALS/FTLD [13, 38, 51], for which three disease mechanisms have been proposed: toxicity of RNA foci formed by RNA repeats, toxicity induced by dipeptide repeat aggregation as a result of repeat associated non-ATG mediated RNA translation (RAN), and reduced expression of the C9orf72 gene [26, 39]. Recently, several animal models have been established to investigate repeat associated gain of toxicity [10, 18, 31, 33, 35, 47] as well as the physiological functions of C9orf72 in mammals. While neuron and glia specific C9orf72 ablation or intracerebral mRNA knockdown does not seem to cause motor neuron disease in mouse models [22, 24], two recent studies on whole body C9orf72 deficient mice demonstrate that C9orf72 deficiency results in severe immune dysregulation [2, 34], suggesting that loss of C9orf72 function could lead to mis-regulated inflammatory responses.
Despite many attempts at characterizing the exact molecular function of C9orf72, its cellular role is still not entirely clear. Bioinformatics studies have predicted C9orf72 to be a member of DENN domain containing proteins which typically function as guanine exchange factors for Rab GTPases, key regulators of membrane trafficking in eukaryotic cells [28, 54]. One study has demonstrated physical interactions between C9orf72 and Rab7 and Rab11, GTPases involved in late endosome maturation or endosome recycling, respectively, and a role of C9orf72 in autophagy regulation . However, direct regulation of these Rab GTPases by C9orf72 was not demonstrated in this study .
In order to gain insight into C9orf72 function, we performed a proteomic screen for C9orf72 binding partners. We showed that C9orf72 forms a tight complex with SMCR8, another DENN domain containing protein , and WDR41, a WD40 repeat protein. We further demonstrated the physical interaction between C9orf72/SMCR8/WDR41 and the FIP200/Ulk1/ATG13/ATG101 complex, which is an essential regulator of autophagy initiation. Our results are consistent with two recent reports on the C9orf72/SMCR8/WDR41 interaction published while this manuscript was under preparation [41, 53]. Furthermore, our data from C9orf72 deficient mice support a role of C9orf72 in immune regulation and the autophagy-lysosome pathway.
Material and methods
DNA and Plasmids
Human C9orf72 (C9-L), WDR41 and SMCR8 cDNAs were from the human ORFome 8.1 library and cloned into pQCXIN, pEGFP-N1 or pEGFP-N2, respectively, with an N-terminal (C9orf72) or C-terminal (WDR41 and SMCR8) GFP tag. The short C9orf72 isoform was cloned from C9-L into pEGFP-C1 with the following 3' primer: tgacCTCGAGttacttgagaagaaagccttcatg. WDR41 and SMCR8 were also cloned into pcDNA3.1 myc his A (Invitrogen) to generate C-terminal myc his tagged constructs. Additionally, C9orf72 and WDR41 were cloned into p3xFLAG-CMV7.1 (Sigma) to generate N-terminal FLAG tagged constructs. Myc-ATG13, FLAG-ATG101 and p3xFLAG-CMV10-hFIP200 were obtained from Addgene (plasmid #31965, 22877 and 24300, respectively).
Pharmacological Reagents and Antibodies
The following primary antibodies were used in this study: anti-FLAG (M2) and anti-myc (9E10) from Sigma-Aldrich, anti-GAPDH from Abcam (ab8245), anti-LC3B (GTX127375) and anti-C9orf72 (GTX119776) from GeneTex, anti-Cathepsin D (sc-6486), anti-Ulk1 (sc-33182) and anti-C9orf72 (sc-138763) from Santa Cruz Biotechnology, anti-C9orf72 (AP12928b) and anti-FIP200 (17250-1-AP) from Proteintech, anti-SMCR8 from Bethyl Laboratories, anti-WDR41 from Abgent, rat anti-CD68 from AbD Serotec, sheep anti-progranulin from R&D systems and anti-mouse LAMP1 (553792) from BD Biosciences. Anti-mouse prosaposin antibody was generated by Pocono Rabbit Farm and Laboratory and was previously characterized . Anti-C9orf72-long isoform  was a gift from Dr. Janice Robertson (University of Toronto); anti-GFP antibody was a gift from Dr. Anthony Bretscher (Cornell University); and anti-GPP130 was a gift from Dr. William Brown (Cornell University). The following secondary antibodies were used: donkey anti-mouse 800 and donkey anti-rabbit 800 from LI-COR, AlexaFluor donkey anti-goat 680, donkey anti-rabbit 680, donkey anti-mouse 680, and donkey anti-rat 680 from Invitrogen, and donkey anti-mouse 568 from Biotium. Hoechst stain was obtained from Invitrogen. Brefeldin A (BFA) and nocodazole were obtained from Sigma-Aldrich and used at a final concentration of 300 μM and 20 mM, respectively.
C9orf72 knockout mice were produced using CRISPR/Cas9 genome editing with a guide RNA (gRNA) targeting exon 2 of mouse gene 3110043O21RIK. C57BL/6 J x FvB/N mouse embryos were injected with gRNA and Cas9 mRNA at the Cornell Transgenic Core Facility. Editing was confirmed by sequencing PCR products from genomic DNA and loss of protein products was determined by Western blot of tissue lysate. Offspring from the founder containing 1 bp deletion were used for the study except the 10 month old founder mice. The following primers were used to genotype C9orf72 knockout mice: 5′- gcggctacctttgcttac -3′ (WT forward), 5′- tggcggctacctttgcta -3 (KO forward) and 5′- tgcccaggagacacaacata -3′ (common reverse).
Cell culture and DNA transfection
HEK293T cells were maintained in Dulbecco’s Modified Eagle’s Medium (Cellgro) supplemented with 10 % fetal bovine serum (Gibco) and 1 % Penicillin–Streptomycin (Invitrogen) in a humidified incubator at 37 °C and 5 % CO2. Cells were transiently transfected with polyethyleneimine as described .
Immunoprecipitation and protein analysis
Cells were lysed in 50 mM Tris pH 8.0, 150 mM NaCl, 1 % Triton X-100, and 0.1 % deoxycholic acid with protease inhibitors (Roche). Lysates were incubated with GFP-Trap beads (ChromoTek) or anti-FLAG antibody conjugated beads (Sigma-Aldrich) for 2–3 h at 4 °C. Beads were washed 3 times with 50 mM Tris pH 8.0, 150 mM NaCl, and 1 % Triton X-100. Samples were denatured in 2xSDS sample buffer (4 % SDS, 20 % glycerol, 100 mM Tris pH 6.8, 0.2 g/L bromophenol blue) by boiling for 3 min. Samples were run on 8 % or 12 % polyacrylamide gels and transferred to PVDF membranes (Millipore). Membranes were blocked in either Odyssey Blocking Buffer (LI-COR Biosciences) or 5 % non-fat milk in PBS for 1 h followed by incubation with primary antibodies overnight at 4 °C. Membranes were washed 3 times with Tris-buffered saline with 0.1 % Tween-20 (TBST) then incubated with secondary antibody for 2 h at room temperature. Membranes were washed 3 times with TBST and imaged using an Odyssey Infrared Imaging System (LI-COR Biosciences).
To quantify protein levels in tissue samples, tissues were homogenized in RIPA buffer (50 mM Tris pH 8.0, 150 mM NaCl, 1 % Triton X-100, 0.1 % SDS and 0.1 % deoxycholic acid) with protease inhibitors on ice and then equal volume of 2X SDS sample buffer was added before sonication. 50 μg of each protein sample was loaded onto a 12 % poly-acrylamide gel. Blots were analyzed by LiCor Odyssey system and normalized to GAPDH.
SILAC and mass spectrometry analysis
N2a cells were grown a minimum of five generations in DMEM with 10 % dialyzed FBS (Sigma) supplemented with either light (C12, N14 arginine and lysine) or heavy (C13, N15 arginine and lysine) amino acids. The heavy cells were transfected in two 15 cm dishes with GFP-C9orf72 expression constructs while the light cells were transfected with pEGFP-C1 as a control. Two days after transfection, cells were lysed in 50 mM Tris pH8.0, 150 mM NaCl, 1 % Triton, 0.1 % deoxycholic acid with protease inhibitors (Roche). The lysates were subject to anti-GFP immunoprecipitation using GFP-Trap beads (ChromoTek). The presence of GFP and GFP-C9orf72 in immunoprecipitated samples was confirmed by SDS-PAGE and Krypton staining (Invitrogen). Samples were then combined and boiled 5 min with 1 % DTT followed by alkylation by treating samples with a final concentration of 28 mM iodoacetamide. Proteins were precipitated on ice for 30 min with a mixture of 50 % acetone/49.9 % ethanol/0.1 % acetic acid. Proteins were pelleted and washed with this buffer, re-precipitated on ice, and dissolved in 8 M urea/50 mM Tris pH 8.0 followed by dilution with three volumes of 50 mM Tris pH 8.0/150 mM NaCl. Proteins were digested overnight at 37 ° C with 1 μg mass-spec grade Trypsin (Promega). The resulting peptide samples were cleaned up for mass spectrometry by treatment with 10 % formic acid and 10 % trifluoroacetic acid (TFA) and washed twice with 0.1 % acetic acid on pre-equilibrated Sep-Pak C18 cartridges (Waters). Samples were eluted with 80 % acetonitrile (ACN)/0.1 % acetic acid into silanized vials (National Scientific) and evaporated using a SpeedVac. Samples were re-dissolved in H2O with ~1 % formic acid and 70 % ACN. Peptides were separated using hydrophilic interaction liquid chromatography (HILIC) on an Ultimate 300 LC (Dionex). Each fraction was evaporated with a SpeedVac and resuspended in 0.1 % TFA with 0.1 pM angiotensin internal standard. Samples were run on a Thermo LTQ Orbitrap XL mass spectrometer and data analyzed using the SORCERER system (Sage-N research).
Hematoxylin and eosin (H&E) staining
Mouse tissues were fixed with 4 % formaldehyde. After dehydration with 70 % ethanol, tissues were embedded with paraffin. The tissues were sliced to 8 μm. Followed by deparaffiinization with xylene and ethanol (100 %, 95 %, 80 %) and rehydration with tap water, the slides were stained in hematoxalin for 3 min, destained with acid ethanol and rinsed with tap water, and then stained with eosin for 30 s. The slides were then dehydrated with ethanol and xylene and mounted.
HeLa cells grown on glass coverslips were fixed in 3.7 % paraformaldehyde for 15 min, washed 3 times with PBS, and permeabilized and blocked in Odyssey Blocking Buffer with 0.05 % saponin or 0.1 % Triton for 20 min. Primary antibodies diluted in blocking buffer with 0.05 % saponin were applied to the cells overnight at 4 °C. Coverslips were washed 3 times with PBS. Secondary antibodies and Hoechst stain diluted in blocking buffer with 0.05 % saponin were applied to the cells for 2 h at room temperature. Coverslips were washed and mounted onto slides with Fluoromount G (Southern Biotech). Images were acquired on a CSU-X spinning disc confocal microscope (Intelligent Imaging Innovations) with an HQ2 CCD camera (Photometrics) using a 100x objective.
Mouse tissues were perfused and fixed with 4 % formaldehyde. After gradient dehydration with 15 % and 30 % sucrose, tissues were embedded with OCT compound (Sakura Finetek USA) and sectioned with Cryotome. For the immunostaining, tissue sections were permeabilized and blocked in Odyssey blocking buffer with 0.05 % saponin for 1 h. Primary antibodies were incubated in blocking buffer overnight at 4 °C. Sections were washed and incubated in secondary antibodies conjugated to Alexaflour 488, 568, or 660 (Invitrogen). Sections were washed three more times and coverslips mounted onto slides with Fluoromount G (Southern Biotech). Images were acquired on a CSU-X spinning disc confocal microscope (Intelligent Imaging Innovations) with an HQ2 CCD camera (Photometrics) using a 40x objective.
The data were presented as mean ± SEM. Two-group analysis was performed using the Student’s t test. P-values <0.05 were considered statistically significant.
C9orf72 forms a complex with SMCR8 and WDR41
Cellular localization of C9orf72, SMCR8 and WDR41
Interaction of C9orf72/SMCR8/WDR41 with the FIP200 autophagy initiation complex
Generation and characterization of C9orf72 deficient mice
Our C9orf72 deficient mice do not have any apparent growth defects (data not shown) but display an obvious lymph node and spleen enlargement phenotype (Fig. 5d), consistent with recent reports on another two independent lines of C9orf72 knockout mice [2, 34]. While occasional mild splenomegaly was observed in the 2 month old C9orf72 deficient mice, this phenotype becomes more severe with age, with the 4-5 month old C9orf72 deficient mouse having a spleen 2-3 times the size of its littermate control (Fig. 5d and Additional file 4: Figure S3). This is also seen in two of the 10 month old founder mice from the CRISPR mediated editing (Additional file 4: Figure S3). The liver also shows slight enlargement but there are no obvious gross anatomical defects in the brain of C9orf72 deficient mice (data not shown).
Autophagy and lysosome defects in the C9orf72 deficient mice
The cellular function of C9orf72 has been under intensive investigation since hexanucleotide repeat expansion in the C9orf72 gene was shown to be the main cause of ALS/FTLD [13, 38, 51], with reduced C9orf72 expression proposed as one of the disease mechanisms . In this study, we searched for protein interactors for C9orf72 and identified SMCR8 and WDR41 as two binding partners of C9orf72, consistent with two recently published reports [41, 53]. We further demonstrated that C9orf72/SMCR8/WDR41 interacts with the FIP200/Ulk1/ATG13/ATG101 complex involved in autophagy initiation. Our data also showed that C9orf72 deficient mice display defects in autophagy/lysosome pathway, supporting a critical role of C9orf72 in autophagy/lysosome regulation.
Many other genes involved in membrane trafficking and autophagy have been associated with ALS/FTLD, including TBK1, OPTN, SQSTM1/p62, UBQLN2, VCP/p97 and CHMP2B [19, 27, 36, 40]. Progranulin, the gene mutated in a vast majority of FTLD with ubiquitin positive TDP-43 aggregates, was recently shown to play a critical role in regulating lysosomal function [8, 42] and the progranulin protein was shown to reside in the lysosome [17, 55]. TMEM106B, a risk factor for FTLD with progranulin mutations, also regulates lysosomal morphology and function [6, 9, 20, 25, 43]. Our current results further support that dysfunction in the autophagy lysosome pathway is implicated in the disease progression of ALS/FTLD caused by C9orf72 mutations. C9orf72 deficiency in C. elegans and zebrafish has been shown to result in locomotion defects [11, 46], supporting the notion that C9orf72 haploinsufficiency could contribute to ALS/FTLD progression. While neuron and glia specific C9orf72 ablation or intracerebral mRNA knockdown does not seem to cause motor neuron disease in mouse models [22, 24], our data and recent data by others consistently demonstrate that whole body C9orf72 deficiency produces severe immune dysregulation in mice [2, 34]. In one study, lysosomal abnormalities were also observed in microglia isolated from C9orf72 deficient mice and in the motor cortex and spinal cord of ALS patients with C9orf72 mutations . These findings strongly suggest that C9orf72 may regulate motor neuron survival through regulation of inflammatory responses by affecting autophagy-lysosomal function of microglia and macrophages. In contrast, our studies failed to detect any obvious abnormalities of microglia in our C9orf72 deficient mice (Fig. 9). It is possible that this may simply be due to our mice not being old enough (10 months old) for us to detect a microglial phenotype. It is also likely that microglial abnormalities may become apparent in the C9orf72 deficient mice upon additional insults to the nervous system.
The physical interaction between the C9orf72/SMCR8/WDR41 complex and the autophagy initiation complex FIP200/Ulk1/ATG13/ATG101 (Fig. 4) suggests that C9orf72/SMCR8/WDR41 might regulate autophagy through the FIP200/Ulk1/ATG13/ATG101 complex. However, exactly how C9orf72/SMCR8/WDR41 regulates autophagy remains unclear. It is interesting that WDR41 is enriched at the Golgi, as the ER-Golgi intermediate compartment has been shown to serve as a key membrane source for autophagosome biogenesis . One possibility is that C9orf72/SMCR8/WDR41 serves as a substrate and a downstream signaling component after Ulk1 activation. Interestingly, SMCR8 was shown to be a substrate for Ulk1 in a recent study . This observation together with reduced autophagy initiation in C9or72-/- spleen tissues argues that C9orf72/SMCR8/WDR41 functions downstream of Ulk1 activation during autophagy activation. Autophagy defects in C9orf72-/- mice might trigger upregulation of autophay/lysosome genes to compensate for the defect. Although we failed to identify any Rab GTPases as C9orf72 interactors in our proteomic screen, C9orf72/SMCR8/WDR41 was shown to interact with Rab8a and Rab39b and functions as a guanine nucleotide exchange factor (GEF) for Rab GTPases in a recent study . However, the effect of Ulk1 phosphorylation on the GEF activities remains to be determined. Future endeavors are needed to further understand the mechanistic functions and regulations of C9orf72/SMCR8/WDR41 complex at molecular and cellular levels. More studies are also needed to characterize neuronal and microglial phenotypes due to C9orf72 loss, possibly upon additional challenges, to explain how C9orf72 deficiency contributes to ALS/FTLD progression.
We describe the identification of two binding partners for C9orf72: SMCR8 and WDR41. We demonstrated that C9orf72/SMCR8/WDR41 interacts with the FIP200/Ulk1/ATG13/ATG101 complex. We also generated C9orf72 deficient mice and showed that loss of C9orf72 leads to macrophage infiltration in multiple organs. Additionally, C9orf72 deficiency leads to autophagy defects and increased levels of many lysosomal proteins, supporting a critical role of C9orf72 in regulating autophagy/lysosomal pathway and inflammation in vivo.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
We thank Dr. Haiyuan Yu (Cornell University) for cDNAs; Dr. Janice Robertson (University of Toronto), Dr. Anthony Bretscher and Dr. William Brown (Cornell University) for antibodies; and Ms. Xiaochun Wu for technical assistance. This work is supported by funding to F.H. from the Weill Institute for Cell and Molecular Biology, the Muscular Dystrophy Association and NINDS (R01NS088448-01) and by funding to X. Z. from the Weill Institute Fleming Postdoctoral Fellowship.
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