TFG Promotes Organization of Transitional ER and Efficient Collagen Secretion

McCaughey, Janine; Miller, Victoria J.; Stevenson, Nicola; Brown, Anna K.; Budnik, Annika; Heesom, Kate J; Alibhai, Dominic; Stephens, David

doi:10.1016/j.celrep.2016.04.062

Cited by 58 publications

(72 citation statements)

References 46 publications

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“…1D and Fig. S1C), consistent with recently published findings (47). However, upon more penetrant inhibition of TFG, as determined by immunofluorescence studies (Fig.…”

Section: Tfg Facilitates the Export Of Conventional Cargoes From The Ersupporting

confidence: 81%

“…A recent study suggested that TFG acts specifically to regulate the transport of large cargoes (47). However, our findings are inconsistent with this idea.…”

Section: Discussioncontrasting

confidence: 57%

“…Additionally, early embryo lethality observed upon TFG knockout in rodents is inconsistent with the more subtle impacts of deleting receptors known to regulate the secretion of large cargoes (53,55). In contrast to our studies, the prior report failed to use immunofluorescence to determine the degree to which TFG was depleted in cells, raising the distinct possibility that TFG was only partially reduced (47). In this scenario, the specific impact on collagen secretion may have been indirectly caused by disruption of exit site organization as a result of long-term partial depletion of TFG, which could disproportionately affect the export of large cargoes over others.…”

Section: Discussioncontrasting

confidence: 52%

“…Additionally, we found that penetrant depletion of TFG disrupts early secretory pathway integrity, leading to the accumulation of inner and outer COPII-coated transport carriers away from the ER/ERGIC interface (44,46). A recent report similarly demonstrated that TFG promotes organization of ER exit sites but suggested a specialized function for TFG in the export of large cargoes, such as procollagens (47). To test directly the contribution of TFG to COPII-dependent cargo transport, we used a reconstituted system in which permeabilized cells lacking cytosol were supplemented with purified recombinant components (10,11,48).…”

Section: Tfg Facilitates the Export Of Conventional Cargoes From The Ermentioning

confidence: 76%

“…In general, current models depicting the ER/ERGIC interface fail to account for the spatial and temporal relationships between COPII coat disassembly and the local retention of transport carriers before target membrane fusion (14,30,34,47,60). Based largely on work conducted in yeast, which lack ERGIC membranes, a stepwise transport mechanism has been proposed that relies on sequential interactions between the inner COPII coat protein Sec23 and three distinct binding partners: Sar1, TRAPPC3, and casein kinase 1δ (14,61).…”

Section: Discussionmentioning

confidence: 99%

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TFG facilitates outer coat disassembly on COPII transport carriers to promote tethering and fusion with ER–Golgi intermediate compartments

Hanna

Block

Frankel

et al. 2017

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

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The conserved coat protein complex II (COPII) mediates the initial steps of secretory protein trafficking by assembling onto subdomains of the endoplasmic reticulum (ER) in two layers to generate cargo-laden transport carriers that ultimately fuse with an adjacent ER–Golgi intermediate compartment (ERGIC). Here, we demonstrate that Trk-fused gene (TFG) binds directly to the inner layer of the COPII coat. Specifically, the TFG C terminus interacts with Sec23 through a shared interface with the outer COPII coat and the cargo receptor Tango1/cTAGE5. Our findings indicate that TFG binding to Sec23 outcompetes these other associations in a concentration-dependent manner and ultimately promotes outer coat dissociation. Additionally, we demonstrate that TFG tethers vesicles harboring the inner COPII coat, which contributes to their clustering between the ER and ERGIC in cells. Together, our studies define a mechanism by which COPII transport carriers are retained locally at the ER/ERGIC interface after outer coat disassembly, which is a prerequisite for fusion with ERGIC membranes.

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“…1D and Fig. S1C), consistent with recently published findings (47). However, upon more penetrant inhibition of TFG, as determined by immunofluorescence studies (Fig.…”

Section: Tfg Facilitates the Export Of Conventional Cargoes From The Ersupporting

confidence: 81%

“…A recent study suggested that TFG acts specifically to regulate the transport of large cargoes (47). However, our findings are inconsistent with this idea.…”

Section: Discussioncontrasting

confidence: 57%

Section: Discussioncontrasting

confidence: 52%

Section: Tfg Facilitates the Export Of Conventional Cargoes From The Ermentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

TFG facilitates outer coat disassembly on COPII transport carriers to promote tethering and fusion with ER–Golgi intermediate compartments

Hanna

Block

Frankel

et al. 2017

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

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Continuum of phenotypes in hereditary motor and sensory neuropathy with proximal predominance and Charcot–Marie–Tooth patients with TFG mutation

Khani

Taheri

Shamshiri

et al. 2019

American J of Med Genetics Pt A

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Charcot-Marie-Tooth (CMT) is a common neuropathy, and hereditary motor and sensory neuropathy with proximal predominance (HMSN-P) is a recently described rare neuromuscular disease. Although many genes have been implicated for CMT, TFG is the only known HMSN-P-causing gene. Within the framework of diagnostic criteria, clinical variation is evident among CMT-diagnosed and also HMSN-P-diagnosed individuals. Mutations that cause p.(Pro285Leu) and p.(Gly269Val) in TFG were earlier reported as cause of HMSN-P in two Iranian pedigrees. Here, we report the identification of p.(Gly269Val) in TFG as cause of CMT in a large Iranian pedigree. The clinical features of patients of the three pedigrees are presented and critically compared. Similarities between the two HMSN-P-diagnosed pedigrees with different TFG mutations, and differences between the two differentially diagnosed pedigrees with the same p.(Gly269Val) mutation were evident. The clinical features of the HMSN-P pedigree with the p.(Pro285Leu) and the CMT pedigree with the p.(Gly269Val) mutation were clearly congruent with the respective diagnoses, whereas the features of the HMSN-P-diagnosed pedigree with the p.(Gly269Val) were intermediate between the other two pedigrees. It is therefore suggested that the clinical features of the three Iranian pedigrees with TFG mutations and diagnosed with HMSN-P or CMT represent a continuum.

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Developing pathways to clarify pathogenicity of unclassified variants in Osteogenesis Imperfecta genetic analysis

Balasubramanian

Hobson

Skae

et al. 2019

Molec Gen & Gen Med

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BackgroundWith increased access to genetic testing, variants of uncertain significance (VUS) where pathogenicity is uncertain are being increasingly identified. More than 85% Osteogenesis Imperfecta (OI) patients have pathogenic variants in COL1A1/A2. However, when a VUS is identified, there are no pathways in place for determining significance.ObjectiveDefine a diagnostic pathway to confirm pathogenicity, providing patients with definitive genetic diagnosis, accurate recurrence risks, and prenatal testing options.MethodsFunctional studies on collagen secretion from cultured patient fibroblasts combined with detailed phenotyping and segregation family studies.ResultsWe demonstrate data from a family with a VUS identified in type I collagen.Family‐1Six‐year‐old boy with failure‐to‐gain weight, talipes, fractures, on and off treatment with Pamidronate as diagnosis of OI uncertain. Transiliac bone biopsy at 2 years of age demonstrated active new bone formation within periosteum; bone cortices were normal thickness but increased porosity. Trabecular bone showed features of advanced osteoporosis. Genetic testing identified a de novo COL1A1 c.206_208delTGT, p.Leu69del variant. Sibling with similar phenotype but no fractures as yet, tested positive for variant raising concerns regarding her diagnosis, and management.Results from three independent experiments (cell immunofluorescence, collagen secretion assay by Western Blot, and unbiased proteomics) from cultured patient fibroblasts demonstrate COL1A1 c.206_208delTGT, p.Leu69del variant causing a substantial defect to collagen extracellular matrix assembly confirming variant pathogenicity.ConclusionAccess to genetic testing in OI is increasing as advances in genetic technologies decreases cost; a clinical diagnostic pathway needs to be implemented for managing variants identified by such testing.

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TFG Promotes Organization of Transitional ER and Efficient Collagen Secretion

Cited by 58 publications

References 46 publications

TFG facilitates outer coat disassembly on COPII transport carriers to promote tethering and fusion with ER–Golgi intermediate compartments

TFG facilitates outer coat disassembly on COPII transport carriers to promote tethering and fusion with ER–Golgi intermediate compartments

Continuum of phenotypes in hereditary motor and sensory neuropathy with proximal predominance and Charcot–Marie–Tooth patients with TFG mutation

Developing pathways to clarify pathogenicity of unclassified variants in Osteogenesis Imperfecta genetic analysis

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