TANGO1 Facilitates Cargo Loading at Endoplasmic Reticulum Exit Sites

Saito, Kota; Chen, Mei; Bard, Fred G.; Chen, Sheng‐Hong; Zhou, Huilin; Woodley, David T.; Polischuk, R; Schekman, Randy; Malhotra, Vivek

doi:10.1016/j.cell.2008.12.025

Cited by 339 publications

(550 citation statements)

References 30 publications

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“…2A). Tango1 is an essential ER/Golgi transmembrane protein originally identified in a Drosophila cell culture screen for genes that influence constitutive secretion and Golgi apparatus structure (7); the mammalian ortholog of Tango1 (Mia3) is essential for the vesicular packaging and secretion of collagen and other high molecular weight proteins (20)(21)(22). We next made antibodies to the C-terminal (CAb) and N-terminal (NAb) regions of Tango1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Roles for Tango1 in constitutive secretion, Golgi structure, and COPII vesicle formation have been identified previously (7,(20)(21)(22), but the factors that regulate its activity and stability are not completely understood. Here, we demonstrate that Tango1 stability is modulated by the competing activities of a specific O-glycosyltransferase (PGANT4) and a specific furin (Dfur2) in secretory cells of the Drosophila digestive tract.…”

Section: Resultsmentioning

confidence: 99%

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O-Glycosylation regulates polarized secretion by modulating Tango1 stability

Zhang

Syed

Härd

et al. 2014

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

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Polarized secretion is crucial in many tissues. The conserved protein modification, O-glycosylation, plays a role in regulating secretion. However, the mechanisms by which this occurs are unknown. Here, we demonstrate that an O-glycosyltransferase functions as a novel regulator of secretion and secretory vesicle formation in vivo by glycosylating the essential Golgi/endoplasmic reticulum protein, Tango1 (Transport and Golgi organization 1), and conferring protection from furin-mediated proteolysis. Loss of the O-glycosyltransferase PGANT4 resulted in Tango1 cleavage, loss of secretory granules, and disrupted apical secretion. The secretory defects seen upon loss of pgant4 could be rescued either by overexpression of Tango1 or by knockdown of a specific furin (Dfur2) in vivo. Our studies elucidate a novel regulatory mechanism whereby secretion is influenced by the yin/yang of O-glycosylation and proteolytic cleavage. Moreover, our data have broader implications for the potential treatment of diseases resulting from the loss of O-glycosylation by modulating the activity of specific proteases.R egulation of secretory vesicle formation and polarized secretion in vivo is crucial to ensure the proper deposition of signaling molecules, morphogens, and matrix components that mediate growth and differentiation. Polarized secretion is also required in many differentiated tissues, such as the digestive tract, where secreted components along the apical surface form the mucous membrane that confers protection from mechanical and microbial insults (1) and provides immunoregulatory signals (2). Indeed, disruptions in the secreted mucous membrane are associated with diseases of the digestive tract, such as colitis and colon cancer (3-6).Recent studies aimed at identifying the factors that influence secretion have elucidated novel proteins that function in unique aspects of secretion, including the enzymes responsible for the addition of sugars to mucins and other proteins (mucin-type O-glycosylation) (7). O-glycosylation is an essential, evolutionarily conserved protein modification (8, 9) that has direct medical relevance, as aberrations are responsible for the human diseases familial tumoral calcinosis (10, 11) and Tn syndrome (12). Loss of this protein modification affected constitutive secretion and Golgi apparatus structure in Drosophila cell culture (7, 13) and secretion in the developing respiratory system in vivo (14). Additionally, loss of O-glycosylation also disrupted secretion of an extracellular matrix protein (Tiggrin) in the developing wing, resulting in aberrant basement membrane formation and disrupted integrin-mediated cell adhesion (15). Mammalian studies have confirmed the effects of O-glycosylation on secretion, as loss of a glycosyltransferase (ppGalNAcT-1) disrupted secretion of laminin and collagen during mammalian organogenesis, altering the composition of the basement membrane and disrupting proper FGF signaling and organ growth (16). Although these studies all point to a role for O-glycosylation in se...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

O-Glycosylation regulates polarized secretion by modulating Tango1 stability

Zhang

Syed

Härd

et al. 2014

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

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“…Expression of meningioma-expressed antigen 6 (Mea6), also known as cutaneous T cell lymphoma-associated antigen 5C (cTAGE5C), is upregulated in different tumor tissues or cell lines, and Mea6 is considered as an oncogene [22][23][24]. Mea6 has been shown to interact with transport and Golgi organization 1 (TANGO1) to facilitate collagen export from the cell [25][26][27][28]. Deletion of TANGO1 in mice results in defects in collagen secretion similar to the phenotype associated with defect in COPII function [29,30].…”

Section: Introductionmentioning

confidence: 99%

Mea6 controls VLDL transport through the coordinated regulation of COPII assembly

et al. 2016

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Lipid accumulation, which may be caused by the disturbance in very low density lipoprotein (VLDL) secretion in the liver, can lead to fatty liver disease. VLDL is synthesized in endoplasmic reticulum (ER) and transported to Golgi apparatus for secretion into plasma. However, the underlying molecular mechanism for VLDL transport is still poorly understood. Here we show that hepatocyte-specific deletion of meningioma-expressed antigen 6 (Mea6)/cutaneous T cell lymphoma-associated antigen 5C (cTAGE5C) leads to severe fatty liver and hypolipemia in mice. Quantitative lipidomic and proteomic analyses indicate that Mea6/cTAGE5 deletion impairs the secretion of different types of lipids and proteins, including VLDL, from the liver. Moreover, we demonstrate that Mea6/cTAGE5 interacts with components of the ER coat protein complex II (COPII) which, when depleted, also cause lipid accumulation in hepatocytes. Our findings not only reveal several novel factors that regulate lipid transport, but also provide evidence that Mea6 plays a critical role in lipid transportation through the coordinated regulation of the COPII machinery.

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“…Tubular-saccular carriers containing procollagen arise from specialized ER domains (1,2). TANGO1 recruits Sedlin and steers procollagen into COPII-dependent ER exit sites (3,4) before CUL3-KLHL12 ubiquitinates a pool of sec31 molecules to drive procollagen transport from the ER to the Golgi apparatus (reviewed by ref. 5).…”

mentioning

confidence: 99%

Nonmuscle myosin II powered transport of newly formed collagen fibrils at the plasma membrane

Kalson

Starborg

et al. 2013

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

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Collagen fibrils can exceed thousands of microns in length and are therefore the longest, largest, and most size-pleomorphic protein polymers in vertebrates; thus, knowing how cells transport collagen fibrils is essential for a more complete understanding of protein transport and its role in tissue morphogenesis. Here, we identified newly formed collagen fibrils being transported at the surface of embryonic tendon cells in vivo by using serial block facescanning electron microscopy of the cell-matrix interface. Newly formed fibrils ranged in length from ∼1 to ∼30 μm. The shortest (1-10 μm) occurred in intracellular fibricarriers; the longest (∼30 μm) occurred in plasma membrane fibripositors. Fibrils and fibripositors were reduced in numbers when collagen secretion was blocked. ImmunoEM showed the absence of lysosomal-associated membrane protein 2 on fibricarriers and fibripositors and there was no effect of leupeptin on fibricarrier or fibripositor number and size, suggesting that fibricarriers and fibripositors are not part of a fibril degradation pathway. Blebbistatin decreased fibricarrier number and increased fibripositor length; thus, nonmuscle myosin II (NMII) powers the transport of these compartments. Inhibition of dynamin-dependent endocytosis with dynasore blocked fibricarrier formation and caused accumulation of fibrils in fibripositors. Data from fluid-phase HRP electron tomography showed that fibricarriers could originate at the plasma membrane. We propose that NMII-powered transport of newly formed collagen fibrils at the plasma membrane is fundamental to the development of collagen fibril-rich tissues. A NMII-dependent cell-force model is presented as the basis for the creation and dynamics of fibripositor structures.3View | SBF-SEM | extracellular matrix | vesicle | actin C ells have sophisticated mechanisms for transporting proteins from one location to another, often within membrane-bound vesicles that need to be of appropriate size and shape to accommodate the cargo. Collagen is a special case and is used as a model protein for studying protein transport; not only is collagen the most abundant structural protein in vertebrates, but it is too large to be accommodated within conventional transport vesicles. Moreover, collagen molecules self-assemble into structures of increasing size with each successive stage in the secretory pathway. The transported cargo increases from ∼0.5 MDa in the endoplasmic reticulum (ER) to several teradaltons (TDa) at the plasma membrane where the molecules are organized into fibrils. The motivation for our study was to build a temporal, spatial, and directional road map of the movement of membrane-bound collagen fibrils at the plasma membrane as the basis for a complete understanding of how cells transport collagen in the process of assembling a mechanically functional extracellular matrix (ECM).In brief, procollagen (the biosynthetic precursor of collagen) is synthesized in the ER and is asymmetric and relatively large; triple helical procollagen molecules are ∼1.5...

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TANGO1 Facilitates Cargo Loading at Endoplasmic Reticulum Exit Sites

Cited by 339 publications

References 30 publications

O-Glycosylation regulates polarized secretion by modulating Tango1 stability

O-Glycosylation regulates polarized secretion by modulating Tango1 stability

Mea6 controls VLDL transport through the coordinated regulation of COPII assembly

Nonmuscle myosin II powered transport of newly formed collagen fibrils at the plasma membrane

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