Receptor-Mediated ER Export of Lipoproteins Controls Lipid Homeostasis in Mice and Humans

Xiao, Wang; Wang, Huimin; Xu, Bing; Huang, Dong; Nie, Chao; Pu, Longjun; Zajac, Gregory J.M.; Yan, Han; Zhao, Jingru; Shi, Fang-Yuan; Emmer, Brian T.; Lu, Jia; Wang, Rui; Dong, Xiaohui; Dai, Jianye; Zhou, Wenjing; Chu, Wenhui; Gao, Ge; Wang, Yan; Willer, Cristen J.; Lu, Xiangfeng; Zhu, Yuangang; Chen, Xiao Wei

doi:10.1016/j.cmet.2020.10.020

Cited by 72 publications

(77 citation statements)

References 66 publications

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“…ERGIC53 regulates ER export of blood coagulation factors V and VIII, a cathepsin-Z–related protein, and alpha1-antittrypsin ( 4 – 7 ). Another cargo receptor, SURF4, binds amino-terminal tripeptide motifs of soluble cargo proteins and regulates ER export of soluble cargo proteins, including the yolk protein VIT-2 in Caenorhabditis elegans ( 8 ), and PCSK9 and apolipoprotein B in mammalian cells ( 9 – 11 ).…”

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confidence: 99%

An in vitro vesicle formation assay reveals cargo clients and factors that mediate vesicular trafficking

Huang

Yin

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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The fidelity of protein transport in the secretory pathway relies on the accurate sorting of proteins to their correct destinations. To deepen our understanding of the underlying molecular mechanisms, it is important to develop a robust approach to systematically reveal cargo proteins that depend on specific sorting machinery to be enriched into transport vesicles. Here, we used an in vitro assay that reconstitutes packaging of human cargo proteins into vesicles to quantify cargo capture. Quantitative mass spectrometry (MS) analyses of the isolated vesicles revealed cytosolic proteins that are associated with vesicle membranes in a GTP-dependent manner. We found that two of them, FAM84B (also known as LRAT domain containing 2 or LRATD2) and PRRC1, contain proline-rich domains and regulate anterograde trafficking. Further analyses revealed that PRRC1 is recruited to endoplasmic reticulum (ER) exit sites, interacts with the inner COPII coat, and its absence increases membrane association of COPII. In addition, we uncovered cargo proteins that depend on GTP hydrolysis to be captured into vesicles. Comparing control cells with cells depleted of the cargo receptors, SURF4 or ERGIC53, we revealed specific clients of each of these two export adaptors. Our results indicate that the vesicle formation assay in combination with quantitative MS analysis is a robust and powerful tool to uncover novel factors that mediate vesicular trafficking and to uncover cargo clients of specific cellular factors.

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confidence: 99%

An in vitro vesicle formation assay reveals cargo clients and factors that mediate vesicular trafficking

Huang

Yin

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…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. 25,26 In this paper, we demonstrate that Surf4 significantly promotes Yamanaka factor-mediated iPSC generation via activation of the response to ER stress.…”

Section: Introductionmentioning

confidence: 99%

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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“…Although progranulin is a glycoprotein and thus a candidate for binding to ERGIC-53 which recognizes cargoes based on their glycosylation, progranulin’s dependence on prosaposin for ER exit, argued against direct binding of progranulin to ERGIC-53 as a major route of ER exit. We therefore focused on Surf4, a receptor for a growing list of ER cargoes 25–28 .…”

Section: Resultsmentioning

confidence: 99%

Surf4 Promotes Endoplasmic Reticulum Exit of the Lysosomal Prosaposin-Progranulin Complex

Devireddy

Ferguson

2021

Preprint

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Progranulin is a lysosomal protein whose haploinsufficiency causes frontotemporal dementia while homozygous loss of progranulin causes neuronal ceroid lipofuscinosis, a lysosomal storage disease. The sensitivity of cells to progranulin deficiency raises important questions about how cells coordinate intracellular trafficking of progranulin to ensure its efficient delivery to lysosomes. In this study, we discover that progranulin interacts with prosaposin, another lysosomal protein, within the lumen of the endoplasmic reticulum (ER) and that prosaposin is required for the efficient ER exit of progranulin. Mechanistically, we identify an interaction between prosaposin and Surf4, a receptor that promotes loading of lumenal cargos into COPII coated vesicles, and establish that Surf4 is critical for the efficient export of progranulin and prosaposin from the ER. Collectively, this work demonstrates a network of interactions occurring early in the secretory pathway that promote the ER exit and subsequent lysosomal delivery of newly translated progranulin and prosaposin.

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Receptor-Mediated ER Export of Lipoproteins Controls Lipid Homeostasis in Mice and Humans

Cited by 72 publications

References 66 publications

An in vitro vesicle formation assay reveals cargo clients and factors that mediate vesicular trafficking

An in vitro vesicle formation assay reveals cargo clients and factors that mediate vesicular trafficking

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

Surf4 Promotes Endoplasmic Reticulum Exit of the Lysosomal Prosaposin-Progranulin Complex

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