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Inceptor binds to and directs insulin towards lysosomal degradation in beta-cells

ABSTRACT: Inceptor binds to and directs insulin towards lysosomal degradation in beta-cells

PROVIDER: PRJNA939837 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23649157_1.fastq.gz	Fastqsanger.gz
	SRR23649157_2.fastq.gz	Fastqsanger.gz
	SRR23649158_1.fastq.gz	Fastqsanger.gz
	SRR23649158_2.fastq.gz	Fastqsanger.gz
	SRR23649159_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Inceptor binds to and directs insulin towards lysosomal degradation in beta-cells

Project description:Blunted first-phase insulin secretion and insulin deficiency are indicators of β-cell dysfunction and diabetes manifestation. Thus, insights into molecular mechanisms that regulate insulin homeostasis might provide entry sites to replenish insulin content and restore β-cell function. Here, we identify the insulin inhibitory receptor (short: inceptor; encoded by the gene IIR) as an insulin-binding receptor that regulates insulin stores by lysosomal degradation. Using human induced pluripotent stem cell (iPSC)-derived islets, we show that IIR knockout (KO) results in enhanced stem cell (SC)-β-cell differentiation and survival. Strikingly, extended in vitro culture of IIR KO SC-β-cells leads to greatly increased insulin content and glucose-stimulated insulin secretion (GSIS). We find that inceptor localises to clathrin-coated vesicles (CCVs) close to the plasma membrane (PM) and in the trans-Golgi network (TGN), as well as in secretory granules (SGs), where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation. Targeting inceptor using a monoclonal antibody (mAB) increases proinsulin and insulin content and improves SC-β-cell GSIS.

2024-09-16 | GSE226346 | GEO

Inceptor binds and directs insulin to lysosomal degradation in -cells

Project description:Blunted first-phase insulin secretion and insulin deficiency are early signs of -cell dysfunction and diabetes manifestation. Thus, insights into molecular mechanisms that regulate insulin homeostasis might provide entry sites to replenish insulin content and restore -cell function. Here, we identified the insulin inhibitory receptor (short: inceptor; encoded by the gene IIR) as an insulin-binding receptor that regulates insulin stores by lysosomal degradation. Using human induced pluripotent stem cell (iPSC)-derived islets, we show that IIR knockout (KO) results in enhanced stem cell (SC)--cell differentiation, maturation, and survival. Strikingly, extended in vitro culture of IIR KO SC--cells leads to greatly increased insulin content and glucose-stimulated insulin secretion (GSIS). We find inceptor localized to clathrin-coated vesicles close to the plasma membrane (PM) and in the trans-Golgi network (TGN), as well as in secretory granules (SGs), where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation. Targeting inceptor using a monoclonal antibody increases insulin content and improves SC--cell function. Altogether, our findings revealed basic mechanisms of -cell insulin turnover and identified inceptor as a druggable insulin degradation receptor.

2024-09-09 | PXD040758 | Pride

Kim et al. STRIPAK directs PP2A activity towards MAP4K4 to promote oncogenic transformation

Project description:STRIPAK directs PP2A activity towards MAP4K4 to promote oncogenic transformation

2019-10-04 | MSV000084422 | MassIVE

Transcription profiling of human 239T cells shows SUMOylation of DRIL1 directs its transcriptional activity towards leukocyte lineage-specific genes

Project description:SUMOylation of DRIL1 directs its transcriptional activity towards leukocyte lineage-specific genes

2009-06-26 | E-TABM-681 | biostudies-arrayexpress

Hypoxia directs human villous CTB differentiation towards the EVT lineage in a HIF-dependent manner.

Project description:We showed that hypoxia directs first trimester primary villous cytotrophoblast (vCTB) differentiation preferentially towards HLAG+ extravillous trophoblast (EVT). Infection of primary vCTB with ARNT-specific shRNA attenuates this effect, suggesting a role of the intact HIF-complex in hypoxia-directed CTB differentiation into EVT.

2017-02-01 | GSE80995 | GEO

Zuo1 supports G4 structure formation and directs repair towards nucleotide excision repair

Project description:Zuo1 supports G4 structure formation and directs repair towards nucleotide excision repair

| PRJNA628932 | ENA

IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin.

Project description:Endoplasmic reticulum (ER) is responsible for folding of secreted and membrane proteins in eukaryotic cells. Disruption of ER protein folding leads to ER stress. Chronic ER stress can cause cell death and is proposed to underlie the pathogenesis of many human diseases. Inositol-requiring enzyme 1 (IRE1) directs a key unfolded protein response signaling pathway that controls the fidelity of ER protein folding. IRE1 signaling may be particularly helpful in preventing chronic ER stress and cell injury by alleviating protein misfolding in the ER. To examine this, we used a chemical-genetic approach to selectively activate IRE1 in mammalian cells and tested how artificial IRE1 signaling affected the fate of misfolded P23H rhodopsin linked to photoreceptor cell death. We found that IRE1 signaling robustly promoted the degradation of misfolded P23H rhodopsin without affecting its wild-type counterpart. We also found that IRE1 used both proteasomal and lysosomal degradation pathways to remove P23H rhodopsin. Surprisingly, when one degradation pathway was compromised, IRE1 signaling could still promote misfolded rhodopsin degradation using the remaining pathway. Last, we showed that IRE1 signaling also reduced levels of several other misfolded rhodopsins with lesser effects on misfolded cystic fibrosis transmembrane conductance regulator. Our findings reveal the diversity of proteolytic mechanisms used by IRE1 to eliminate misfolded rhodopsin.

| S-EPMC3290636 | biostudies-literature

mTORC1 feedback to AKT modulates MiT/TFE-driven lysosomal biogenesis and EGFR degradation

Project description:MiT/TFE transcriptional activity controls lysosomal biogenesis and is negatively regulated by the nutrient sensor mTORC1. Some tumors bypass this regulatory circuit via genetic alterations that drive MiT/TFE expression and activity; however, the mechanisms by which cells with intact or constitutive mTORC1 signaling maintain lysosomal catabolism remain to be elucidated. Using the murine epidermis as a model system, we find that epidermal Tsc1 deletion results in a wavy hair phenotype due to increased EGFR degradation. Unexpectedly, constitutive mTORC1 activation increases lysosomal content via up-regulated expression and activity of MiT/TFEs, while genetic or prolonged pharmacologic mTORC1 inactivation has the reverse effect. This paradoxical up-regulation of lysosomal biogenesis by mTORC1 is mediated by feedback inhibition of AKT, and a resulting suppression of AKT-induced MiT/TFE proteasomal degradation. These data suggest that oncogenic feedback loops work to restrain or maintain cellular lysosomal content during chronically inhibited or constitutively active mTORC1 signaling respectively, and reveal a mechanism by which mTORC1 regulates upstream receptor tyrosine kinase signaling.

2020-04-14 | GSE124754 | GEO

A lysosomal delivery mechanism required for autophagosome degradation

Project description:A lysosomal delivery mechanism required for autophagosome degradation

| PRJEB62651 | ENA

ActVI-ORFA directs metabolic flux towards actinorhodin by preventing intermediate degradation.

Project description:The biosynthetic pathway of actinorhodin in Streptomyces coelicolor A3(2) has been studied for decades as a model system of type II polyketide biosynthesis. The actinorhodin biosynthetic gene cluster includes a gene, actVI-orfA, that encodes a protein that belongs to the nuclear transport factor-2-like (NTF-2-like) superfamily. The function of this ActVI-ORFA protein has been a long-standing question in this field. Several hypothetical functions, including pyran ring cyclase, enzyme complex stability enhancer, and gene transcription regulator, have been proposed for ActVI-ORFA in previous studies. However, although the recent structural analysis of ActVI-ORFA revealed a solvent-accessible cavity, the protein displayed structural differences to the well-characterized cyclase SnoaL and did not possess a DNA-binding domain. The obtained crystal structure facilitates an inspection of the previous hypotheses regarding the function of ActVI-ORFA. In the present study, we investigated the effects of a series of actVI-orfA test plasmids with different mutations in an established vector/host system. Time-course analysis of dynamic metabolism profiles demonstrated that ActVI-ORFA prevented formation of shunt metabolites and may have a metabolic flux directing function, which shepherds the flux of unstable intermediates towards actinorhodin. The expression studies resulted in the isolation and structure elucidation of two new shunt metabolites from the actinorhodin pathway. Next, we utilized computational modeling to probe the active site of ActVI-ORFA and confirmed the importance of residues R76 and H78 in the flux directing functionality by expression studies. This is the first time such a function has been observed for a member of NTF-2-like superfamily in Streptomyces secondary metabolism.

| S-EPMC11315284 | biostudies-literature

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