Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cideb controls sterol-regulated ER export of SREBP/SCAP by promoting cargo loading at ER exit sites

ABSTRACT: SREBPs are master regulators of lipid homeostasis and undergo sterol-regulated export from ER to Golgi apparatus for processing and activation via COPII-coated vesicles. While COPII recognizes SREBP through its escort protein SCAP, factor(s) specifically promoting SREBP/SCAP loading to the COPII machinery remains unknown. Here, we show that the ER/lipid droplet associated protein Cideb selectively promotes the loading of SREBP/SCAP into COPII vesicles. Sterol deprivation releases SCAP from Insig and enhances ER export of SREBP/SCAP by inducing SCAP-Cideb interaction, thereby modulating sterol sensitivity. Moreover, Cideb binds to the guanine nucleotide exchange factor Sec12 to enrich SCAP/SREBP at ER exit sites, where assembling of COPII complex initiates. Loss of Cideb inhibits the cargo loading of SREBP/SCAP, reduces SREBP activation, and alleviates diet-induced hepatic steatosis. Our data point to a linchpin role of Cideb in regulated ER export of SREBP and lipid homeostasis.

SUBMITTER: Peng Li

PROVIDER: S-SCDT-EMBOJ-2018-100156 | biostudies-other |

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Cideb controls sterol-regulated ER export of SREBP/SCAP by promoting cargo loading at ER exit sites.

Project description:SREBPs are master regulators of lipid homeostasis and undergo sterol-regulated export from ER to Golgi apparatus for processing and activation via COPII-coated vesicles. While COPII recognizes SREBP through its escort protein SCAP, factor(s) specifically promoting SREBP/SCAP loading to the COPII machinery remains unknown. Here, we show that the ER/lipid droplet-associated protein Cideb selectively promotes the loading of SREBP/SCAP into COPII vesicles. Sterol deprivation releases SCAP from Insig and enhances ER export of SREBP/SCAP by inducing SCAP-Cideb interaction, thereby modulating sterol sensitivity. Moreover, Cideb binds to the guanine nucleotide exchange factor Sec12 to enrich SCAP/SREBP at ER exit sites, where assembling of COPII complex initiates. Loss of Cideb inhibits the cargo loading of SREBP/SCAP, reduces SREBP activation, and alleviates diet-induced hepatic steatosis. Our data point to a linchpin role of Cideb in regulated ER export of SREBP and lipid homeostasis.

| S-EPMC6463267 | biostudies-literature

Tango1 spatially organizes ER exit sites to control ER export.

Project description:Exit of secretory cargo from the endoplasmic reticulum (ER) takes place at specialized domains called ER exit sites (ERESs). In mammals, loss of TANGO1 and other MIA/cTAGE (melanoma inhibitory activity/cutaneous T cell lymphoma-associated antigen) family proteins prevents ER exit of large cargoes such as collagen. Here, we show that Drosophila melanogaster Tango1, the only MIA/cTAGE family member in fruit flies, is a critical organizer of the ERES-Golgi interface. Tango1 rings hold COPII (coat protein II) carriers and Golgi in close proximity at their center. Loss of Tango1, present at ERESs in all tissues, reduces ERES size and causes ERES-Golgi uncoupling, which impairs secretion of not only collagen, but also all other cargoes we examined. Further supporting an organizing role of Tango1, its overexpression creates more and larger ERESs. Our results suggest that spatial coordination of ERES, carrier, and Golgi elements through Tango1's multiple interactions increases secretory capacity in Drosophila and allows secretion of large cargo.

| S-EPMC5379956 | biostudies-literature

SFT-4/Surf4 control ER export of soluble cargo proteins and participate in ER exit site organization.

Project description:Lipoproteins regulate the overall lipid homeostasis in animals. However, the molecular mechanisms underlying lipoprotein trafficking remain poorly understood. Here, we show that SFT-4, a Caenorhabditis elegans homologue of the yeast Erv29p, is essential for the endoplasmic reticulum (ER) export of the yolk protein VIT-2, which is synthesized as a lipoprotein complex. SFT-4 loss strongly inhibits the ER exit of yolk proteins and certain soluble cargo proteins in intestinal cells. SFT-4 predominantly localizes at ER exit sites (ERES) and physically interacts with VIT-2 in vivo, which suggests that SFT-4 promotes the ER export of soluble proteins as a cargo receptor. Notably, Surf4, a mammalian SFT-4 homologue, physically interacts with apolipoprotein B, a very-low-density lipoprotein core protein, and its loss causes ER accumulation of apolipoprotein B in human hepatic HepG2 cells. Interestingly, loss of SFT-4 and Surf4 reduced the number of COPII-positive ERES. Thus, SFT-4 and Surf4 regulate the export of soluble proteins, including lipoproteins, from the ER and participate in ERES organization in animals.

| S-EPMC5987718 | biostudies-literature

Contact of cis-Golgi with ER exit sites executes cargo capture and delivery from the ER.

Project description:Protein transport from the endoplasmic reticulum (ER) to the Golgi apparatus is mediated by coat complex II (COPII) vesicles. It has been believed that COPII vesicles containing cargo are released from the ER exit sites (ERES) into the cytosol and then reach and fuse with the first post-ER compartment, cis-Golgi or ER-to-Golgi intermediate compartment (ERGIC). However, it still remains elusive how cargo loading to vesicles, vesicle budding, tethering and fusion are coordinated in vivo. Here we show, using extremely high speed and high resolution confocal microscopy, that the cis-Golgi in the budding yeast Saccharomyces cerevisiae approaches and contacts the ERES. The COPII coat cage then collapses and the cis-Golgi captures cargo. The cis-Golgi, thus loaded with cargo, then leaves the ERES. We propose that this 'hug-and-kiss' behaviour of cis-Golgi ensures efficient and targeted cargo transport from the ERES to cis-Golgi.

| S-EPMC3996532 | biostudies-literature

Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.

Project description:Leucine-rich repeat kinase 2 (LRRK2) has been associated with Parkinson's disease (PD) and other disorders. However, its normal physiological functions and pathogenic properties remain elusive. Here we show that LRRK2 regulates the anterograde ER-Golgi transport through anchoring Sec16A at the endoplasmic reticulum exit sites (ERES). LRRK2 interacted and co-localized with Sec16A, a key protein in the formation of ERES. Lrrk2 depletion caused a dispersion of Sec16A from ERES and impaired ER export. In neurons, LRRK2 and Sec16A showed extensive co-localization at the dendritic ERES (dERES) that locally regulate the transport of proteins to the dendritic spines. A loss of Lrrk2 affected the association of Sec16A with dERES and impaired the activity-dependent targeting of glutamate receptors onto the cell/synapse surface. Furthermore, the PD-related LRRK2 R1441C missense mutation in the GTPase domain interfered with the interaction of LRRK2 with Sec16A and also affected ER-Golgi transport, while LRRK2 kinase activity was not required for these functions. Therefore, our findings reveal a new physiological function of LRRK2 in ER-Golgi transport, suggesting ERES dysfunction may contribute to the pathogenesis of PD.

| S-EPMC4253522 | biostudies-literature

Sec16 defines endoplasmic reticulum exit sites and is required for secretory cargo export in mammalian cells.

Project description:The selective export of proteins and lipids from the endoplasmic reticulum (ER) is mediated by the coat protein complex II (COPII) that assembles onto the ER membrane. In higher eukaryotes, COPII proteins assemble at discrete sites on the membrane known as ER exit sites (ERES). Here, we identify Sec16 as the protein that defines ERES in mammalian cells. Sec16 localizes to ERES independent of Sec23/24 and Sec13/31. Overexpression, and to a lesser extent, small interfering RNA depletion of Sec16, both inhibit ER-to-Golgi transport suggesting that Sec16 is required in stoichiometric amounts. Sar1 activity is required to maintain the localization of Sec16 at discrete locations on the ER membrane, probably through preventing its dissociation. Our data suggest that Sar1-GTP-dependent assembly of Sec16 on the ER membrane forms an organized scaffold defining an ERES.

| S-EPMC1761133 | biostudies-literature

Concentration of Sec12 at ER exit sites via interaction with cTAGE5 is required for collagen export.

Project description:Mechanisms for exporting variably sized cargo from the endoplasmic reticulum (ER) using the same machinery remain poorly understood. COPII-coated vesicles, which transport secretory proteins from the ER to the Golgi apparatus, are typically 60-90 nm in diameter. However, collagen, which forms a trimeric structure that is too large to be accommodated by conventional transport vesicles, is also known to be secreted via a COPII-dependent process. In this paper, we show that Sec12, a guanine-nucleotide exchange factor for Sar1 guanosine triphosphatase, is concentrated at ER exit sites and that this concentration of Sec12 is specifically required for the secretion of collagen VII but not other proteins. Furthermore, Sec12 recruitment to ER exit sites is organized by its direct interaction with cTAGE5, a previously characterized collagen cargo receptor component, which functions together with TANGO1 at ER exit sites. These findings suggest that the export of large cargo requires high levels of guanosine triphosphate-bound Sar1 generated by Sec12 localized at ER exit sites.

| S-EPMC4164946 | biostudies-literature

The sterol-sensing endoplasmic reticulum (ER) membrane protein TRC8 hampers ER to Golgi transport of sterol regulatory element-binding protein-2 (SREBP-2)/SREBP cleavage-activated protein and reduces SREBP-2 cleavage.

Project description:TRC8 (translocation in renal cancer from chromosome 8) is an intrinsic protein of the endoplasmic reticulum that contains a sterol-sensing domain and a RING finger motif encoding an E3 ubiquitin ligase. Here we show that TRC8 overexpression hinders sterol regulatory element-binding protein-2 (SREBP-2) processing, thereby reducing SREBP-2 target gene expression, TRC8 depletion has the opposite effect. Mutation analyses of TRC8 reveal that the ubiquitin ligase activity is dispensable for these effects. Activating transcription factor 6 (ATF6) is also processed in the Golgi by the same two proteases as those for SREBP, but ATF6 processing is not affected by TRC8. TRC8 is capable of binding both SREBP-2 and SREBP cleavage-activated protein (SCAP), thereby forming a TRC8.SREBP-2.SCAP complex. This complex formation hampers the interaction between SCAP and Sec24, one of the COPII proteins that are involved in SREBP-2 transport to the Golgi, thereby reducing SREBP-2 cleavage. TRC8 conjugated by ubiquitin is unstable, whereas the mutant TRC8, lacking the E3 ubiquitin ligase activity and only slightly modified by ubiquitin, is quite stable. TRC8 becomes stable when cells are cultured with a proteasome inhibitor or under a lipoprotein-depleted condition. Lipoprotein depletion impairs ubiquitination of TRC8. Taken together, TRC8 is a novel sterol-sensing endoplasmic reticulum membrane protein that hinders SREBP-2 processing through interaction with SREBP-2 and SCAP, regulating its own turnover rate by means of its E3 ubiquitin ligase activity.

| S-EPMC2781446 | biostudies-literature

Carbohydrate- and conformation-dependent cargo capture for ER-exit.

Project description:Some secretory proteins leave the endoplasmic reticulum (ER) by a receptor-mediated cargo capture mechanism, but the signals required for the cargo-receptor interaction are largely unknown. Here, we describe a novel targeting motif that is composed of a high-mannose type oligosaccharide intimately associated with a surface-exposed peptide beta-hairpin loop. The motif accounts for lectin ERGIC-53-assisted ER-export of the lyososomal enzyme procathepsin Z. The second oligosaccharide chain of procathepsin Z exhibits no binding activity for ERGIC-53, illustrating the selective lectin properties of ERGIC-53. Our data suggest that the conformation-based motif is only present in fully folded procathepsin Z and that its recognition by ERGIC-53 reflects a quality control mechanism that acts complementary to the primary folding machinery in the ER. A similar oligosaccharide/beta-hairpin loop structure is present in cathepsin C, another cargo of ERGIC-53, suggesting the general nature of this ER-exit signal. To our knowledge this is the first documentation of an ER-exit signal in soluble cargo in conjunction with its decoding by a transport receptor.

| S-EPMC551490 | biostudies-literature

ER arrival sites associate with ER exit sites to create bidirectional transport portals.

Project description:COPI vesicles mediate Golgi-to-ER recycling, but COPI vesicle arrival sites at the ER have been poorly defined. We explored this issue using the yeast Pichia pastoris. ER arrival sites (ERAS) can be visualized by labeling COPI vesicle tethers such as Tip20. Our results place ERAS at the periphery of COPII-labeled ER export sites (ERES). The dynamics of ERES and ERAS are indistinguishable, indicating that these structures are tightly coupled. Displacement or degradation of Tip20 does not alter ERES organization, whereas displacement or degradation of either COPII or COPI components disrupts ERAS organization. We infer that Golgi compartments form at ERES and then produce COPI vesicles to generate ERAS. As a result, ERES and ERAS are functionally linked to create bidirectional transport portals at the ER-Golgi interface. COPI vesicles likely become tethered while they bud, thereby promoting efficient retrograde transport. In mammalian cells, the Tip20 homologue RINT1 associates with ERES, indicating possible conservation of the link between ERES and ERAS.

| S-EPMC7147096 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data