<i>cTAGE5</i> deletion in pancreatic β cells impairs proinsulin trafficking and insulin biogenesis in mice

Fan, Junwan; Wang, Yaqing; Liu, Liang; Zhang, Hongsheng; Zhang, Feng; Shi, Lei; Yu, Mei; Gao, Fei; Xu, Zhiheng

doi:10.1083/jcb.201705027

Cited by 36 publications

(42 citation statements)

References 51 publications

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“…In contrast, the deletion of cTage5 is embryonically lethal . Conditional deletion of cTage5 in insulin producing pancreatic beta cells leads to inhibition of proinsulin secretion, suggesting a role of cTage5 in adaptation to high volume secretion . The conditional deletion of cTage5 in the liver, leads to the development of fatty liver and hypolipemia, derived from inhibited secretion of VLDL and attenuated exit of apolipoprotein B100 from the ER .…”

Section: The Molecular Architecture Of Er Exit Sitesmentioning

confidence: 99%

“…Not surprisingly, primer proteins, that control the initial steps in coat assembly, also control the morphological organization of the ER‐Golgi secretion hub . TANGO1 utilizes its first CC to maintain membrane contacts between ERES and ERGIC membranes (Figures A and A).…”

Section: The Roles Of Membrane Organization In Trafficmentioning

confidence: 99%

“…Membrane contacts within the ERES secretion hub are further maintained by cTage5. The second CC of cTage5 interacts with the SNARE protein Sec22b, which functions at the ER‐Golgi interface, linking ERES and ERGIC membranes (Figure A) . TANGO1 also interacts with the TRAPP tether complex, which is involved in anterograde traffic from ERES and membrane contacts formed by TRAPP‐driven interactions regulate COPII assembly .…”

Section: The Roles Of Membrane Organization In Trafficmentioning

confidence: 99%

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COPII gets in shape: Lessons derived from morphological aspects of early secretion

Aridor

2018

Traffic

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Our view of the secretory pathway has evolved from a morphological one to one that includes molecular mechanistic understanding of basic traffic components. These components include coat complexes involved in cargo sorting and budding and proteins that mediate targeting, tethering and fusion. The expanding repertoire of regulators that control basic traffic activities begins to paint a unified morphological-molecular view of secretion. The emerging picture provides key insights into the coupling of secretion with physiology. This review examines aspects of morphological-molecular relations that are derived from studies on traffic from the endoplasmic reticulum carried by the coat protein complex II.

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Section: The Molecular Architecture Of Er Exit Sitesmentioning

confidence: 99%

Section: The Roles Of Membrane Organization In Trafficmentioning

confidence: 99%

Section: The Roles Of Membrane Organization In Trafficmentioning

confidence: 99%

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COPII gets in shape: Lessons derived from morphological aspects of early secretion

Aridor

2018

Traffic

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“…These data argue for a broader role for Tango1/cTage5 in ER export, beyond regulation of large cargo transport. Consistent with this idea, elimination of cTage5 in pancreatic beta cells results in impaired insulin trafficking, and depletion of Tango1 delays export of small cargoes from the ER, including VSVG . The question now shifts to what actually regulates constriction and scission of large COPII transport carriers.…”

Section: Introductionmentioning

confidence: 86%

Membrane Transport at an Organelle Interface in the Early Secretory Pathway: Take Your Coat Off and Stay a While

et al. 2018

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Most metazoan organisms have evolved a mildly acidified and calcium diminished sorting hub in the early secretory pathway commonly referred to as the Endoplasmic Reticulum-Golgi intermediate compartment (ERGIC). These membranous vesicular-tubular clusters are found tightly juxtaposed to ER subdomains that are competent for the production of COPII-coated transport carriers. In contrast to many unicellular systems, metazoan COPII carriers largely transit just a few hundred nanometers to the ERGIC, prior to COPI-dependent transport on to the cis-Golgi. The mechanisms underlying formation and maintenance of ERGIC membranes are poorly defined. However, recent evidence suggests an important role for Trk-fused gene (TFG) in regulating the integrity of the ER/ERGIC interface. Moreover, in the absence of cytoskeletal elements to scaffold tracks on which COPII carriers might move, TFG appears to promote anterograde cargo transport by locally tethering COPII carriers adjacent to ERGIC membranes. This action, regulated in part by the intrinsically disordered domain of TFG, provides sufficient time for COPII coat disassembly prior to heterotypic membrane fusion and cargo delivery to the ERGIC.

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“…3F), suggesting that CHOP has a long-term effect on “ ER remodeling ”. Since the UPR is an adaptive response to ER stress, we tested biochemically if Chop deleted β cells exhibit reduced ER stress, by probing the interaction between ProIns and BiP, as BiP binding to misfolded proinsulin is the gold-standard biochemical indicator for ER due to ProIns misfolding in the β cell ( 19-21 ). By the BiP co-IP assay, we confirmed that less BiP protein was associated with ProIns in the Chop β KO islets (Fig.…”

Section: Figurementioning

confidence: 99%

Chop/Ddit3depletion in β-cells alleviates ER stress and corrects hepatic steatosis

Yong

Parekh

Nayak

et al. 2020

Preprint

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Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic β cells is enhanced, which can lead to proinsulin (ProIns) misfolding that aggravates endoplasmic reticulum (ER) homeostasis in β cells. Moreover, increased insulin in the circulation may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in β cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that germline Chop gene deletion preserved β cells in high fat diet (HFD) fed mice and in leptin receptor-deficient db/db mice. In the current study, we further investigated whether targeting Chop/Ddit3 specifically in murine β cells confers therapeutic benefits. First, we show that Chop deletion in  cells alleviates β cell ER stress and delays glucose-stimulated insulin secretion (GSIS) in HFD fed mice. Second, importantly, β cell-specific Chop deletion prevented liver steatosis and hepatomegaly in aged HFD fed mice without affecting basal glucose homeostasis. Third, we provide the first mechanistic evidence that ER remodeling secondary to Chop deletion modulates glucose-induced islet Ca 2+ oscillations. Finally, using state-of-the-art GLP1-conjugated Chop AntiSense Oligonucleotides (GLP1-Chop ASO), we demonstrated that the Chop deletion induced GSIS change is a long term complex event in β cells. In summary, our results demonstrate that Chop depletion in β cells is a new therapeutic strategy to alleviate dysregulated insulin secretion and the consequently fatty liver disease in T2D. (245 words)3

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cTAGE5 deletion in pancreatic β cells impairs proinsulin trafficking and insulin biogenesis in mice

Abstract: In this study, Fan et al. show that cTAGE5 interacts with the v-SNARE Sec22b to regulate proinsulin processing and COPII-dependent trafficking from the ER to the Golgi, thereby influencing glucose tolerance.

Cited by 36 publications

References 51 publications

COPII gets in shape: Lessons derived from morphological aspects of early secretion

COPII gets in shape: Lessons derived from morphological aspects of early secretion

Membrane Transport at an Organelle Interface in the Early Secretory Pathway: Take Your Coat Off and Stay a While

Chop/Ddit3depletion in β-cells alleviates ER stress and corrects hepatic steatosis

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