Global defects in collagen secretion in a <i>Mia3/TANGO1</i> knockout mouse

Wilson, Deanna G.; Phamluong, Khanhky; Li, Li; Sun, Mei; Cao, Tiesen; Liu, Peter S.; Modrušan, Zora; Sandoval, Wendy; Rangell, Linda; Carano, Richard A.D.; Peterson, Andrew S.; Solloway, Mark J.

doi:10.1083/jcb.201007162

Cited by 177 publications

(159 citation statements)

References 55 publications

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“…This provides more evidence that Mea6 regulates lipid transport through interaction with COPII subunits. Deletion of Tango1 in mice results in defects in collagen secretion and skeletal development [29]. We have found Mea6 has been implicated as a shorter spliced variant of Mia2, a TANGO1-like protein with similar domains [45].…”

Section: Discussionmentioning

confidence: 88%

“…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]. However, the physiological function of Mea6 is still not clear.…”

Section: Introductionmentioning

confidence: 95%

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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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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 95%

Mea6 controls VLDL transport through the coordinated regulation of COPII assembly

et al. 2016

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“…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%

“…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. Tango1 is a ubiquitously expressed protein that regulates not only constitutive secretion, but also the formation of large secretory vesicles that transport bulky ECM proteins in certain cells (7,(20)(21)(22). Tango1/Mia3 is proposed to bind secretory cargo via its luminal domain and COPII coat subunits via its cytoplasmic domain, thereby coordinating the size of secretory vesicles to accommodate large ECM proteins (20)(21)(22).…”

Section: Resultsmentioning

confidence: 99%

“…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%

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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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Gene‐based association tests in family samples using GWAS summary statistics

Wang,

Xu,

et al. 2024

Genetic Epidemiology

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Genome‐wide association studies (GWAS) have led to rapid growth in detecting genetic variants associated with various phenotypes. Owing to a great number of publicly accessible GWAS summary statistics, and the difficulty in obtaining individual‐level genotype data, many existing gene‐based association tests have been adapted to require only GWAS summary statistics rather than individual‐level data. However, these association tests are restricted to unrelated individuals and thus do not apply to family samples directly. Moreover, due to its flexibility and effectiveness, the linear mixed model has been increasingly utilized in GWAS to handle correlated data, such as family samples. However, it remains unknown how to perform gene‐based association tests in family samples using the GWAS summary statistics estimated from the linear mixed model. In this study, we show that, when family size is negligible compared to the total sample size, the diagonal block structure of the kinship matrix makes it possible to approximate the correlation matrix of marginal Z scores by linkage disequilibrium matrix. Based on this result, current methods utilizing summary statistics for unrelated individuals can be directly applied to family data without any modifications. Our simulation results demonstrate that this proposed strategy controls the type 1 error rate well in various situations. Finally, we exemplify the usefulness of the proposed approach with a dental caries GWAS data set.

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Global defects in collagen secretion in a Mia3/TANGO1 knockout mouse

Abstract: Mia3’s contribution to protein secretion is broader than previously realized—its absence impairs collagen deposition and normal development of cartilage and bone.

Cited by 177 publications

References 55 publications

Mea6 controls VLDL transport through the coordinated regulation of COPII assembly

Mea6 controls VLDL transport through the coordinated regulation of COPII assembly

O-Glycosylation regulates polarized secretion by modulating Tango1 stability

Gene‐based association tests in family samples using GWAS summary statistics

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