Murine Surf4 is essential for early embryonic development

Emmer, Brian T.; Lascuna, Paul J.; Tang, Vi T; Kotnik, Emilee N.; Saunders, Thomas L.; Khoriaty, Rami; Ginsburg, David

doi:10.1371/journal.pone.0227450

Cited by 21 publications

(23 citation statements)

References 48 publications

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“…Indeed, Surf4 is essential for early development in animals. Its homozygous knockout caused embryonic lethality in both Caenorhabditis elegans and mice 26 , 48 , suggesting that Surf4 plays a broader role in protein secretion.…”

Section: Discussionmentioning

confidence: 99%

Cargo receptor Surf4 regulates endoplasmic reticulum export of proinsulin in pancreatic β-cells

et al. 2022

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Insulin is an essential peptide hormone that maintains blood glucose levels. Although the mechanisms underlying insulin exocytosis have been investigated, the mechanism of proinsulin export from the endoplasmic reticulum (ER) remains unclear. Here, we demonstrated that Surf4, a cargo receptor homolog, regulates the ER export of proinsulin via its recruitment to ER exit sites (ERES). Under high-glucose conditions, Surf4 expression was upregulated, and Surf4 proteins mainly localized to the ER at a steady state and accumulated in the ERES, along with proinsulin in rat insulinoma INS-1 cells. Surf4-knockdown resulted in proinsulin retention in the ER and decreased the levels of mature insulin in secretory granules, thereby significantly reducing insulin secretion. Surf4 forms an oligomer and can physically interact with proinsulin and Sec12, essential for COPII vesicle formation. Our findings suggest that Surf4 interacts with proinsulin and delivers it into COPII vesicles for ER export in co-operation with Sec12 and COPII.

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Section: Discussionmentioning

confidence: 99%

Cargo receptor Surf4 regulates endoplasmic reticulum export of proinsulin in pancreatic β-cells

et al. 2022

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“…Recent studies in human cells have also implicated SURF4 in the trafficking of other cargoes, including apolipoprotein B (APOB) (Emmer et al, 2020;Saegusa et al, 2018;, erythropoietin (EPO) (Lin et al, 2020), growth hormone, dentin sialophosphoprotein, and amelogenin (Yin et al, 2018). A role for SURF4 in APOB secretion was further supported by a recent study in which acute deletion of hepatic Surf4 in adult mice caused hypocholesterolemia and a reduction in hepatic lipoprotein secretion (X.…”

Section: Introductionmentioning

confidence: 94%

Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol

Tang

McCormick

et al. 2022

Preprint

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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 (Surf4(fl/fl) Alb-Cre(+)) to investigate the physiologic role of SURF4 in vivo. Surf4(fl/fl) Alb-Cre(+) mice exhibited normal viability, gross development, and fertility. Plasma PCSK9 levels were reduced by ~60% in Surf4(fl/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. Despite a small increase in liver mass and lipid content, histologic evaluation revealed no evidence of steatohepatitis or fibrosis in Surf4(fl/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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“…23 Deficiency of Surf4 in mice results in embryonic lethality after implantation. 21 A study of lipoprotein transport revealed that SURF4-mediated ER export of lipoproteins controls lipid homeostasis in mice and humans. 24 During mouse preimplantation development, Surf4 was highly enriched in MII oocytes 9,25 and early embryos before the two-cell stage.…”

Section: Introductionmentioning

confidence: 99%

“… 13 , 15 , 16 , 17 , 18 , 19 Disruption of Surf4 trafficking results in a reduction in the number of ERGIC clusters 20 and accumulation of cargo proteins in the ER compartment. 21 Dysregulation of ER‐Golgi vesicle transport induces ER stress, 22 and in turn, when ER stress occurs, the expression of Erv29p significantly increases. 23 Deficiency of Surf4 in mice results in embryonic lethality after implantation.…”

Section: Introductionmentioning

confidence: 99%

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Surf4 facilitates reprogramming by activating the cellular response to endoplasmic reticulum stress

et al. 2021

Cell Proliferation

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Objectives: Maternal factors that are enriched in oocytes have attracted great interest as possible key factors in somatic cell reprogramming. We found that surfeit locus protein 4 (Surf4), a maternal factor, can facilitate the generation of induced pluripotent stem cells (iPSCs) previously, but the mechanism remains elusive. Materials and Methods:In this study, we investigated the function and mechanism of Surf4 in somatic cell reprogramming using a secondary reprogramming system.Alkaline phosphatase (AP) staining, qPCR and immunofluorescence (IF) staining of expression of related markers were used to evaluate efficiency of iPSCs derived from mouse embryonic fibroblasts. Embryoid body and teratoma formation assays were performed to evaluate the differentiation ability of the iPSC lines. RNA-seq, qPCR and western blot analysis were applied to validate the downstream targets of Surf4.Results: Surf4 can significantly facilitate the generation of iPSCs in a proliferationindependent manner. When co-expressed with Oct4, Sox2, Klf4 and c-Myc (OSKM), Surf4 can activate the response to endoplasmic reticulum (ER) stress at the early stage of reprogramming. We further demonstrated that Hspa5, a major ER chaperone, and the active spliced form of Xbp1 (sXbp1), a major mediator of ER stress, can mimic the effects of Surf4 on somatic cell reprogramming. Concordantly, blocking the unfolded protein response compromises the effect of Surf4 on reprogramming.

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Murine Surf4 is essential for early embryonic development

Cited by 21 publications

References 48 publications

Cargo receptor Surf4 regulates endoplasmic reticulum export of proinsulin in pancreatic β-cells

Cargo receptor Surf4 regulates endoplasmic reticulum export of proinsulin in pancreatic β-cells

Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol

Surf4 facilitates reprogramming by activating the cellular response to endoplasmic reticulum stress

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