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SignificanceSonic Hedgehog (Shh) is a key signaling molecule that plays important roles in embryonic patterning, cell differentiation, and organ development. Although fundamentally important, the molecular mechanisms that regulate secretion of newly synthesized Shh are still unclear. Our study reveals a role for the cargo receptor, SURF4, in facilitating export of Shh from the endoplasmic reticulum (ER) via a ER export signal. In addition, our study provides evidence suggesting that proteoglycans promote the dissociation of SURF4 from Shh at the Golgi, suggesting a SURF4-to-proteoglycan relay mechanism. These analyses provide insight into an important question in cell biology: how do cargo receptors capture their clients in one compartment, then disengage at their destination?
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Proteínas Hedgehog , Proteínas de Membrana , Proteoglicanas , Retículo Endoplasmático/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Transporte Proteico/fisiologia , Proteoglicanas/metabolismoRESUMO
In the conventional secretory pathway, cargo receptors play important roles in exporting newly synthesized secretory proteins from the endoplasmic reticulum (ER). We previously showed that a cargo receptor, surfeit locus protein 4 (SURF4), promotes ER export of a soluble signaling molecule, sonic hedgehog, via recognizing the polybasic residues within its Cardin-Weintraub motif. In addition to sonic hedgehog, we found 30 more secretory proteins containing the polybasic motif (K/R)(K/R)(K/R)XX(K/R)(K/R), but whether SURF4 plays a general role in mediating ER export of these secretory proteins is unclear. Here, we analyzed the trafficking of four of these secretory proteins: desert hedgehog, Indian hedgehog, bone morphogenetic protein 8A (BMP8A), and secreted frizzled-related protein 1 (SFRP1). We found that the polybasic motifs contained in these cargo proteins are important for their ER export. Further analyses indicated that the polybasic motifs of BMP8A and SFRP1 interact with the triacidic motif on the predicted first luminal domain of SURF4. These interactions with SURF4 are essential and sufficient for the ER-to-Golgi trafficking of BMP8A and SFRP1. Moreover, we demonstrated that SURF4 localizes at a subpopulation of ER exit sites to regulate the ER export of its clients. Taken together, these results suggest that SURF4 is recruited to specific ER exit sites and plays a general role in capturing polybasic motif-containing secretory cargo proteins through electrostatic interactions.
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Retículo Endoplasmático , Proteínas Hedgehog , Humanos , Proteínas Morfogenéticas Ósseas/química , Proteínas Morfogenéticas Ósseas/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Proteínas Hedgehog/química , Proteínas Hedgehog/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Transporte Proteico , Motivos de AminoácidosRESUMO
Proteins that are destined to enter the secretory pathway are synthesized on the rough endoplasmic reticulum (ER) and then translocated into the ER lumen, where they undergo posttranslational modifications, folding, and assembly. After passing a quality control system, the cargo proteins are packaged into coat protein complex II (COPII) vesicles to exit the ER. In metazoans, most COPII subunits have multiple paralogs, enabling COPII vesicles the flexibility to transport a diverse range of cargo. The cytoplasmic domains of transmembrane proteins can interact with SEC24 subunits of COPII to enter the ER exit sites. Some transmembrane proteins may also act as cargo receptors that bind soluble secretory proteins within the ER lumen, enabling them to enter COPII vesicles. The cytoplasmic domains of cargo receptors also contain coat protein complex I binding motifs that allow for their cycling back to the ER after unloading their cargo in the ER-Golgi intermediate compartment and cis-Golgi. Once unloaded, the soluble cargo proteins continue maturation through the Golgi before reaching their final destinations. This review provides an overview of receptor-mediated transport of secretory proteins from the ER to the Golgi, with a focus on the current understanding of two mammalian cargo receptors: the LMAN1-MCFD2 complex and SURF4, and their roles in human health and disease.
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Retículo Endoplasmático , Complexo de Golgi , Animais , Humanos , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Transporte Proteico , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo , Mamíferos/metabolismoRESUMO
Alzheimer's disease (AD) is known to be caused by amyloid ß-peptide (Aß) misfolded into ß-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in Aß toxicity, we carried out a genome-wide screen in Saccharomyces cerevisiae, using a library of 5154 gene knock-out strains expressing Aß1-42. We identified 81 mammalian orthologue genes that enhance Aß1-42 toxicity, while 157 were protective. Next, we performed interactome and text-mining studies to increase the number of genes and to identify the main cellular functions affected by Aß oligomers (oAß). We found that the most affected cellular functions were calcium regulation, protein translation and mitochondrial activity. We focused on SURF4, a protein that regulates the store-operated calcium channel (SOCE). An in vitro analysis using human neuroblastoma cells showed that SURF4 silencing induced higher intracellular calcium levels, while its overexpression decreased calcium entry. Furthermore, SURF4 silencing produced a significant reduction in cell death when cells were challenged with oAß1-42, whereas SURF4 overexpression induced Aß1-42 cytotoxicity. In summary, we identified new enhancer and protective activities for Aß toxicity and showed that SURF4 contributes to oAß1-42 neurotoxicity by decreasing SOCE activity.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Animais , Humanos , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/toxicidade , Peptídeos beta-Amiloides/química , Cálcio/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Morte Celular , Canais de Cálcio/genética , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/toxicidade , Fragmentos de Peptídeos/metabolismo , Mamíferos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismoRESUMO
SURF4, which is located in the Surfeit gene cluster, encodes for a conserved integral membrane protein containing multiple putative transmembrane regions. However, the physiological role of SURF4 has not been determined. We found that SURF4 demonstrated aberrant amplification and increased expression in the tumor tissues of several human cancer patients. Overexpression of SURF4 led to increased cell proliferation, migration, and maintenance of anchorage-independent growth. In addition, NIH3T3 cells overexpressing SURF4 induced tumor growth in the mice. Collectively, our findings demonstrate that SURF4 has the potential for inducing cellular transformation and cell migration in vitro and has oncogenic transformation ability in vivo.
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Carcinogênese/genética , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/genética , Regulação para Cima , Animais , Movimento Celular , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Camundongos , Células NIH 3T3 , Neoplasias/genéticaRESUMO
Surfeit locus protein 4 (SURF4) functions as a cargo receptor that is capable of transporting newly formed proteins from the lumen of the endoplasmic reticulum into vesicles and Golgi bodies. However, the role of SURF4 in the central nervous system remains unclear. The aim of this study is to investigate the role of SURF4 and its underlying mechanisms in cerebral ischemia/reperfusion (I/R) injury in rats, and whether it can be used effectively for novel therapeutic intervention. We also examined whether transcranial direct-current stimulation (tDCS) can exert a neuroprotective effect via SURF4-dependent signalling. Following cerebral I/R injury in rats, a significant increase was observed in the expression of SURF4. In both I/R injury and oxygen-glucose deprivation (OGD) insult, suppressing the expression of SURF4 demonstrated a neuroprotective effect, while overexpression of SURF4 resulted in increased neuronal death. We further showed that the levels of nerve growth factor precursor (proNGF), p75 neurotrophin receptor (p75NTR), sortilin, and PTEN were increased following cerebral I/R injury, and that SURF4 acted through the PTEN/proNGF signal pathway to regulate neuronal viability. We demonstrated that tDCS treatment reduced SURF4 expression and decreased the infarct volume after cerebral I/R injury. Together, this study indicates that SURF4 plays a critical role in ischemic neuronal injury and may serve as a molecular target for the development of therapeutic strategies in acute ischemic stroke.
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Isquemia Encefálica , AVC Isquêmico , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Estimulação Transcraniana por Corrente Contínua , Ratos , Animais , Fármacos Neuroprotetores/farmacologia , Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Isquemia Encefálica/metabolismo , Apoptose , Infarto da Artéria Cerebral Média/metabolismoRESUMO
Surfeit locus protein 4 is a cargo receptor mediating cargo transport from the endoplasmic reticulum lumen to the Golgi apparatus. Loss of Surf4 gene led to embryonic lethality in mice. However, the role of Surf4 during oocyte development remains unknown. In this study, we generated the mouse model with oocyte-specific knockout of Surf4 gene. We found that adult mice with deletion of Surf4 showed normal folliculogenesis, ovulation and fertility. However, loss of Surf4 slightly impaired oocyte quality, thus led to partial oocyte meiotic arrest and reduced ratio of blastocyst formation. Consistent with this, the distribution of endoplasmic reticulum was disturbed in Surf4-deficient oocytes in mice. These results demonstrated that although Surf4 is dispensable for female mouse fertility, Surf4 modulates endoplasmic reticulum arrangement and participates in regulation of developmental competence of oocytes.
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Retículo Endoplasmático , Meiose , Proteínas de Membrana , Camundongos Knockout , Oócitos , Animais , Oócitos/metabolismo , Oócitos/citologia , Feminino , Retículo Endoplasmático/metabolismo , Meiose/genética , Camundongos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Fertilidade/genética , Ovulação/genética , Camundongos Endogâmicos C57BL , Blastocisto/metabolismo , Blastocisto/citologiaRESUMO
OBJECTIVE: Lipoprotein assembly and secretion in the small intestine are critical for dietary fat absorption. Surfeit locus protein 4 (SURF4) serves as a cargo receptor, facilitating the cellular transport of multiple proteins and mediating hepatic lipid secretion in vivo. However, its involvement in intestinal lipid secretion is not fully understood. In this study, we investigated the role of SURF4 in intestinal lipid absorption. METHODS: We generated intestine-specific Surf4 knockout mice and characterized the phenotypes. Additionally, we investigated the underlying mechanisms of SURF4 in intestinal lipid secretion using proteomics and cellular models. RESULTS: We unveiled that SURF4 is indispensable for apolipoprotein transport and lipoprotein secretion. Intestine-specific Surf4 knockout mice exhibited ectopic lipid deposition in the small intestine and hypolipidemia. Deletion of SURF4 impeded the transport of apolipoprotein A1 (ApoA1), proline-rich acidic protein 1 (PRAP1), and apolipoprotein B48 (ApoB48) and hindered the assembly and secretion of chylomicrons and high-density lipoproteins. CONCLUSIONS: SURF4 emerges as a pivotal regulator of intestinal lipid absorption via mediating the secretion of ApoA1, PRAP1 and ApoB48.
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Intestinos , Lipoproteínas , Camundongos , Animais , Apolipoproteína B-48/metabolismo , Lipoproteínas/metabolismo , Quilomícrons/metabolismo , Camundongos Knockout , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismoRESUMO
Background: Alzheimer's disease (AD) is a widespread neurodegenerative disorder with a significant global impact, affecting approximately 50 million individuals, and projections estimate that up to 152 million people will be affected by 2050. AD is characterized by beta-amyloid plaques and tau tangles in the brain, leading to cognitive decline. Summary: Recent research on AD has made significant strides, including the development of an "amyloid clock" biomarker that tracks AD progression through positron emission tomography (PET) scans. Surf4 and other genes have been discovered to play a role in regulating beta-amyloid toxicity, while inhibiting the enzyme hexokinase-2 has shown positive results in preclinical studies. New brain mapping techniques have identified early brain-based causes of cognitive changes in AD, and biomarkers such as neuronal pentraxin protein Nptx2 and astrocytic 7-subunit of the nicotinic acetylcholine receptors (7nAChRs) show potential for early detection. Other approaches, such as replenishing the enzyme Tip60, selectively degrading the modified protein p-p38 with PRZ-18002, and targeting the protein voltage-dependent anion channel-1 (VDAC1), have shown promise in enhancing cognitive function and preventing pathophysiological alterations linked to AD. Baseline blood samples and other biomarkers such as urine formic acid, p-tau 198, microRNAs, and glial fibrillary acidic protein (GFAP) have also been discovered for early detection and intervention of AD. Additionally, recent FDA approvals for medications such as aducanumab and lecanemab provide options for reducing AD symptoms and improving function, while clinical trials for dementia vaccines show promise for the nasal and beta-amyloid 40 vaccines as well as vaccinations targeting tau. Key Messages: These advancements in AD research, including biomarker discovery and the development of disease-modifying treatments, are crucial steps towards improving the lives of those affected by AD and finding a cure for this debilitating disease.
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PCSK9 negatively regulates low-density lipoprotein receptor (LDLR) abundance on the cell surface, leading to decreased hepatic clearance of LDL particles and increased levels of plasma cholesterol. We previously identified SURF4 as a cargo receptor that facilitates PCSK9 secretion in HEK293T cells (Emmer et al., 2018). Here, we generated hepatic SURF4-deficient mice (Surf4fl/fl Alb-Cre+) to investigate the physiologic role of SURF4 in vivo. Surf4fl/fl Alb-Cre+ mice exhibited normal viability, gross development, and fertility. Plasma PCSK9 levels were reduced by ~60% in Surf4fl/fl Alb-Cre+ mice, with a corresponding ~50% increase in steady state LDLR protein abundance in the liver, consistent with SURF4 functioning as a cargo receptor for PCSK9. Surprisingly, these mice exhibited a marked reduction in plasma cholesterol and triglyceride levels out of proportion to the partial increase in hepatic LDLR abundance. Detailed characterization of lipoprotein metabolism in these mice instead revealed a severe defect in hepatic lipoprotein secretion, consistent with prior reports of SURF4 also promoting the secretion of apolipoprotein B (APOB). Despite a small increase in liver mass and lipid content, histologic evaluation revealed no evidence of steatohepatitis or fibrosis in Surf4fl/fl Alb-Cre+ mice. Acute depletion of hepatic SURF4 by CRISPR/Cas9 or liver-targeted siRNA in adult mice confirms these findings. Together, these data support the physiologic significance of SURF4 in the hepatic secretion of PCSK9 and APOB-containing lipoproteins and its potential as a therapeutic target in atherosclerotic cardiovascular diseases.
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Pró-Proteína Convertase 9 , Receptores de LDL , Camundongos , Humanos , Animais , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , RNA Interferente Pequeno/metabolismo , Células HEK293 , Camundongos Endogâmicos C57BL , Receptores de LDL/genética , Receptores de LDL/metabolismo , Fígado/metabolismo , Apolipoproteínas B/metabolismo , Lipoproteínas/metabolismo , Triglicerídeos/metabolismo , Colesterol/metabolismo , Lipoproteínas LDL/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismoRESUMO
SURF4 has been suggested as an oncogene in cancer. However, the role of SURF4 in breast cancer has not been demonstrated yet. The data were obtained from TCGA database and 1104 patients were analyzed using bioinformatics analysis. SURF4 is significantly (P < 0.001) highly expressed in tumor. High expression of SURF4 was observed in T4, infiltrating ductal carcinoma, ER negative, PR negative, and HER2 positive, female, patients without lymph node metastasis, HER2 overexpression type, and deceased patients. As for characteristics correlated with high expression of SURF4, gender, histological type, molecular subtype, ER, PR, HER2, and vital status exhibited significant differences. The age (HR: 2.317, P < 0.001), stage (HR: 2.090, P < 0.001), and SURF4 expression (HR: 1.958, P = 0.005) exhibited independent prognostic value for overall survival (OS). Patients with high SURF4 expression, higher age, equivocal HER2, higher stages, or positive margin status had shorter OS. The stage (HR: 1.579, P < 0.001), and margin status (HR: 1.463, P = 0.006) exhibited independent prognostic value for relapse-free survival of breast cancer. High expression of SURF4 was first found in breast cancer. High SURF4 expression was observed in breast cancer tissue and cell. SURF4 promoted the proliferation and migration of 4T1 cells. SURF4 may be a biomarker in diagnosis and prognosis of breast cancer.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Recidiva Local de Neoplasia , Prognóstico , Metástase Linfática , Biomarcadores Tumorais/genética , Intervalo Livre de Doença , Proteínas de Membrana/genéticaRESUMO
The endoplasmic reticulum (ER)-to-Golgi transport is critical to protein secretion and intracellular sorting. Here, we report a highly elongated tubular ER-Golgi intermediate compartment (t-ERGIC) that selectively expedites the ER-to-Golgi transport for soluble cargoes of the receptor SURF4. Lacking the canonical ERGIC marker ERGIC-53 yet positive for the small GTPases Rab1A/B, the t-ERGIC is further marked by its extraordinarily elongated and thinned shape. With its large surface-to-volume ratio, high intracellular traveling speeds, and ER-Golgi recycling capabilities, the t-ERGIC accelerates the trafficking of SURF4-bound cargoes. The biogenesis and cargo selectivity of t-ERGIC both depend on SURF4, which recognizes the N terminus of soluble cargoes and co-clusters with the selected cargoes to expand the ER-exit site. In the steady state, the t-ERGIC-mediated fast ER-to-Golgi transport is antagonized by the KDEL-mediated ER retrieval. Together, our results argue that specific cargo-receptor interactions give rise to distinct transport carriers that regulate the trafficking kinetics.
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Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , Proteínas de Membrana/metabolismo , Transporte Proteico/fisiologia , Transporte Biológico/fisiologia , Humanos , Proteínas de Transporte Vesicular/metabolismoRESUMO
Circulating polymers of α1-antitrypsin (α1AT) are neutrophil chemo-attractants and contribute to inflammation, yet cellular factors affecting their secretion remain obscure. We report on a genome-wide CRISPR-Cas9 screen for genes affecting trafficking of polymerogenic α1ATH334D. A CRISPR enrichment approach based on recovery of single guide RNA (sgRNA) sequences from phenotypically selected fixed cells reveals that cells with high-polymer content are enriched in sgRNAs targeting genes involved in "cargo loading into COPII-coated vesicles," where "COPII" is coat protein II, including the cargo receptors lectin mannose binding1 (LMAN1) and surfeit protein locus 4 (SURF4). LMAN1- and SURF4-disrupted cells display a secretion defect extending beyond α1AT monomers to polymers. Polymer secretion is especially dependent on SURF4 and correlates with a SURF4-α1ATH334D physical interaction and with their co-localization at the endoplasmic reticulum (ER). These findings indicate that ER cargo receptors co-ordinate progression of α1AT out of the ER and modulate the accumulation of polymeric α1AT not only by controlling the concentration of precursor monomers but also by promoting secretion of polymers.
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Retículo Endoplasmático/metabolismo , Polímeros/metabolismo , alfa 1-Antitripsina/metabolismo , HumanosRESUMO
BACKGROUND & AIMS: A single point mutation in the Z-variant of alpha 1-antitrypsin (Z-AAT) alone can lead to both a protein folding and trafficking defect, preventing its exit from the endoplasmic reticulum (ER), and the formation of aggregates that are retained as inclusions within the ER of hepatocytes. These defects result in a systemic AAT deficiency (AATD) that causes lung disease, whereas the ER-retained aggregates can induce severe liver injury in patients with ZZ-AATD. Unfortunately, therapeutic approaches are still limited and liver transplantation represents the only curative treatment option. To overcome this limitation, a better understanding of the molecular basis of ER aggregate formation could provide new strategies for therapeutic intervention. METHODS: Our functional and omics approaches here based on human hepatocytes from patients with ZZ-AATD have enabled the identification and characterisation of the role of the protein disulfide isomerase (PDI) A4/ERP72 in features of AATD-mediated liver disease. RESULTS: We report that 4 members of the PDI family (PDIA4, PDIA3, P4HB, and TXNDC5) are specifically upregulated in ZZ-AATD liver samples from adult patients. Furthermore, we show that only PDIA4 knockdown or alteration of its activity by cysteamine treatment can promote Z-AAT secretion and lead to a marked decrease in Z aggregates. Finally, detailed analysis of the Z-AAT interactome shows that PDIA4 silencing provides a more conducive environment for folding of the Z mutant, accompanied by reduction of Z-AAT-mediated oxidative stress, a feature of AATD-mediated liver disease. CONCLUSIONS: PDIA4 is involved in AATD-mediated liver disease and thus represents a therapeutic target for inhibition by drugs such as cysteamine. PDI inhibition therefore represents a potential therapeutic approach for treatment of AATD. LAY SUMMARY: Protein disulfide isomerase (PDI) family members, and particularly PDIA4, are upregulated and involved in alpha 1-antitrypsin deficiency (AATD)-mediated liver disease in adults. PDI inhibition upon cysteamine treatment leads to improvements in features of AATD and hence represents a therapeutic approach for treatment of AATD-mediated liver disease.
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OBJECTIVE: As cancer stem cells (CSCs) are considered as the origin of tumor development, recurrence, and drug resistance, we aimed to explore the mechanism related to modulating stemness in CSCs, thus facilitating to search for new therapeutic strategy for ovarian cancer. METHODS: In this study, ovarian cancer stem cells (OCSCs) induced from cell line 3AO and A2780 were enriched in serum-free medium (SFM). The effect of SURF4 on CSC-like properties was evaluated by sphere-forming assays, re-differentiation assays, quantitative real-time polymerase chain reaction, flow cytometry, Western blotting, cell viability assays and in vivo xenograft experiments. The downstream molecule participating in SURF4 maintaining stemness was screened by RNA-sequencing and identified by the experiments of gene function. RESULTS: SURF4 was upregulated expressed in OCSCs. Knockdown of SURF4 reduced the expression of the related stem markers (SOX2 and c-MYC), inhibited self-renewal ability, and improved the sensitivity to chemotherapeutic drugs (paclitaxel and cisplatin) in OCSCs. SURF4 knockdown also inhibited tumorigenesis in nonobese diabetic/severe combined immunodeficiency mice. BIRC3 expression was controlled by SURF4, and BIRC3 showed the similar effect as SURF4 did, and BIRC3 overexpression partially recovered stem-like properties abolished by SURF4 knockdown. CONCLUSION: Our findings suggest that SURF4 possesses the ability to maintain stemness of OCSCs via BIRC3, and may serve as a potential target in stem cell-targeted therapy for ovarian cancer.
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Neoplasias Ovarianas , Animais , Proteína 3 com Repetições IAP de Baculovírus , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Proteínas de Membrana , Camundongos , Recidiva Local de Neoplasia , Células-Tronco NeoplásicasRESUMO
PCSK9 is a secreted protein that regulates plasma cholesterol levels and cardiovascular disease risk. Prior studies suggested the presence of an ER cargo receptor that recruits PCSK9 into the secretory pathway, but its identity has remained elusive. Here, we apply a novel approach that combines proximity-dependent biotinylation and proteomics together with genome-scale CRISPR screening to identify SURF4, a homologue of the yeast cargo receptor Erv29p, as a primary mediator of PCSK9 secretion in HEK293T cells. The functional contribution of SURF4 to PCSK9 secretion was confirmed with multiple independent SURF4-targeting sgRNAs, clonal SURF4-deficient cell lines, and functional rescue with SURF4 cDNA. SURF4 was found to localize to the early secretory pathway where it physically interacts with PCSK9. Deletion of SURF4 resulted in ER accumulation and decreased extracellular secretion of PCSK9. These findings support a model in which SURF4 functions as an ER cargo receptor mediating the efficient cellular secretion of PCSK9.