ERp46 binds to AdipoR1, but not AdipoR2, and modulates adiponectin signalling

Charlton, Hayley K.; Webster, Julie A.; Krüger, Sarah; Simpson, Fiona; Richards, Ayanthi A.; Whitehead, Jonathan P.

doi:10.1016/j.bbrc.2010.01.029

Cited by 59 publications

(78 citation statements)

References 29 publications

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“…In addition to APPL1, other adiponectin receptor interacting proteins have been identified, including the receptor for activated protein kinase C1 (RACK1) [86], the regulatory subunit of protein kinase CK2 (CK2β) [87], endoplasmic reticulum protein 46 (ERp46) [88] and lymphotoxin-β [89]. Of these, binding of lymphotoxin-β to AdipoR1 appears to be involved in adiponectin-mediated suppression of NF-κB signaling in endothelial cells [89].…”

Section: Adiponectin Receptors and Signaling Pathwaysmentioning

confidence: 99%

“…Of these, binding of lymphotoxin-β to AdipoR1 appears to be involved in adiponectin-mediated suppression of NF-κB signaling in endothelial cells [89]. Erp46 has been reported to interact specifically with AdipoR1 via non-conserved N-terminal amino acids, and it is involved in regulating adiponectin-stimulated AMPK and p38 MAPK phosphorylation [88].…”

Section: Adiponectin Receptors and Signaling Pathwaysmentioning

confidence: 99%

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Characterisation of the relationship between Heme-oxygenase-1 and adiponectin

Yang¹

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The prevalence of obesity is growing at an alarming rate worldwide, and current therapies have limited benefits. Therefore, it is essential to increase our understanding of the underlying mechanisms so that new strategies can be developed to reduce the incidence of obesity related diseases. Adiponectin is an adipocyte-derived hormone that regulates glucose and lipid metabolism via direct and indirect mechanisms and has anti-inflammatory, anti-diabetic, anti-atherogenic and cardioprotective properties. Hypoadiponectinemia is implicated in the aetiology of obesity-related diseases making strategies to increase circulating adiponectin levels therapeutically attractive.Emerging evidence, predominantly from preclinical studies, suggests induction of heme-oxygenase-1 (HO-1) increases adiponectin production concomitant with decreased inflammatory tone prompting the proposal of a "HO-1 -adiponectin axis." However, the underlying mechanisms of increased adiponectin production via HO-1 induction are poorly defined; indeed a direct relationship has not been demonstrated. Thus, the overarching aim of this thesis is to investigate the effects of HO-1 induction on adiponectin production as well as adipocyte and adipose tissue remodelling and metabolic parameters using cellular and mouse models.Initial studies were designed to characterize the direct effect of HO-1 induction on adiponectin production. We found that treatment with the widely used HO-1 inducer cobalt protoporphyrin (CoPP) or hemin for 24-48 h increased HO-1 expression and activity without affecting adiponectin expression and secretion, in human mature adipocyte under a variety of experimental scenarios.Treatment of adipocytes with TNFα reduced adiponectin production and induced pro-inflammatory cytokines production. HO-1 induction failed to reverse these effects. These results do not support a direct HO-1 -adiponectin axis.However, literature suggests that chronic induction of HO-1 via CoPP administration throughout differentiation, promotes adiponectin secretion, albeit in the context of reduced adipogenesis. While our previous findings argued against the existence of a direct "HO-1 -adiponectin axis," they did not address the potential effects of chronic induction of HO-1 on adiponectin production. Thus, we extended our study to characterise the effects of chronic HO-1 induction throughout differentiation of human preadipocytes. In this study we demonstrate that chronic induction of HO-1 with CoPP or hemin throughout differentiation results in dose-dependent inhibition of adipogenesis and adiponectin production as well as induction of additional NRF2 target genes. Co-treatment with SnMP (HO-1 activity inhibitor) and HO-1 siRNA did not prevent these effects. These findings suggest that the chronic treatment with CoPP or hemin inhibits adipogenesis and adiponectin production potentially by a HO-1-independent mechanism that may be downstream of NRF2.iii However, our results contradict the majority of reports in the literature. One possibility is that the ...

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Section: Adiponectin Receptors and Signaling Pathwaysmentioning

confidence: 99%

Section: Adiponectin Receptors and Signaling Pathwaysmentioning

confidence: 99%

Characterisation of the relationship between Heme-oxygenase-1 and adiponectin

Yang¹

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“…However, the first 70/81 amino acids of AdipoR1 and AdipoR2 show only 17% homology 70 whilst the rest of the sequences are 95% identical (Figure 1.2).…”

Section: Adiponectin Receptor Structurementioning

confidence: 99%

“…Dimerisation of adiponectin receptors is well established 48,70,151 . In 2010 it was demonstrated that a GxxxG in the 5 th TM of R1 is required for the dimerisation.…”

Section: Receptor Dimerisationmentioning

confidence: 99%

“…The best characterised of these is APPL1 72 , which interacts with both AdipoR1 and AdipoR2 100 . We recently identified ERp46 as an AdipoR1-specific interacting protein and demonstrated that knockdown of ERp46 increased the enrichment of AdipoR1, and AdipoR2, in the plasma membrane (PM) and altered adiponectin signalling 70 . In the current report we have extended these studies by further characterisation of AdipoR1 and AdipoR2 at the level of cellsurface expression.…”

Section: Introductionmentioning

confidence: 99%

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Molecular characterisation of the adiponectin receptors, AdipoR1 and AdipoR2

Keshvari¹

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The increasing global prevalence of cardiovascular and metabolic diseases necessitates the development of more effective therapeutic strategies that, in turn, require a greater understanding of the regulatory networks involved. Research over the last decade has increased our appreciation of the key role of the adiponectin axis as a major regulator of metabolic, cardiovascular and inflammatory tone, thereby establishing it as a province of therapeutic opportunity. The receptors for adiponectin, AdipoR1 and AdipoR2, are distant relatives of the largest single class of drug targets, the G-protein coupled receptor (GPCR) family. However, unlike GPCRs they have intracellular N-termini and extracellular C-termini and signal via atypical pathways. Our current understanding of AdipoR1 and AdipoR2 is rudimentary, constraining our ability to target these receptors effectively. The aim of this thesis was to characterise molecular features of AdipoR1 and AdipoR2 that facilitate adiponectin signal transduction to advance our understanding and identify strategies to enhance adiponectin's beneficial effects.We have begun to characterise basic properties of AdipoR1 and AdipoR2, focusing on molecular factors that drive cell-surface expression (CSE) of the receptors using a range of C-terminal, epitope-tagged AdipoR1 and AdipoR2 constructs. Surprisingly, under steady-state conditions (no serum starvation) only AdipoR1 was readily detected on the cell-surface (cell-surface ratio of AdipoR1 vs AdipoR2 is 0.6±0.1 vs 0.15±0.1, p<0.05). Generation and characterisation of a series of chimeric and truncated constructs demonstrated that a non-conserved, intracellular, N-terminal region of AdipoR2 (R2 ) restricted its CSE whilst the same region in AdipoR1 (R1 (1-70) ) promoted its CSE. We also confirmed that AdipoR1 and AdipoR2 form heterodimer and that coexpression of these receptors increase the CSE of AdipoR2. Subsequently, we provided evidence that the subcellular localisation of AdipoR1 and AdipoR2 is governed by multiple motifs across their non-conserved and conserved cytoplasmic domains. For instance, two highly conserved motifs, an ER exit motif (FxxxFxxxF) and Di-Leucine motif (DxxxLL), in the conserved Nterminal domain are required for the proper CSE of both AdipoR1 and AdipoR2, whilst different parts of the non-conserved domain of AdipoR2 inhibits its CSE.Moreover, we demonstrated that in HEK-293 cells over-expressing AdipoR1 adiponectin activated downstream signalling networks (AMPK, AKT, ERK & P38MAPK) acutely (peaking at 15 min) whereas signal transduction via AdipoR2 was relatively chronic (peaking at 24 h). This difference was also underpinned by the non-conserved N-terminal domains of AdipoR1 and AdipoR2. We also demonstrated that a number of conserved and non-conserved cysteines in the N-terminal domain of iii AdipoR1 and AdipoR2 are subject to palmitoylation and that palmitoylation of a conserved cysteine, situated in the juxta-membrane region of the N-termini of AdipoR1 and AdipoR2 in a position analogous to t...

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Identification of thioredoxin domain containing family members' expression pattern and prognostic value in diffuse gliomas via in silico analysis

Kocatürk

2022

Cancer Medicine

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Background Gliomas are the most prevalent primary tumors of the central nervous system. Their aggressive nature and the obstacles arising during therapy highlights the importance of finding new prognostic markers and therapy targets for gliomas. TXNDC genes are members of the thioredoxin superfamily and were shown to play a role in redox homeostasis, protein folding, electron transfer and also acting as cellular adapters. The well known contribution of these processes in cancer progression prompted us to investigate if TXNDC family members may also play a role in carcinogenesis, in particular diffuse gliomas. Methods The present study used in silico analysis tools GEPIA, UCSC Xena, Gliovis, cBioPortal, and Ivy GAP to evaluate the expression pattern, prognostic value and clinical significance of TXNDC family members in diffuse gliomas. Results Our analysis showed that TXNDC family members' expression pattern differ between tumors and healthy tissues and among tumors with different grades. The detailed analysis of TXNDC5 in glioma pathogenesis revealed that TXNDC5 expression is associated with more aggressive clinical and molecular features and poor therapy success both in LGG and GBM samples. Kaplan–Meier survival curves represented a worse prognosis for patients with leveated TXNDC5 levels in LGG and all grade glioma patients. The levels of TXNDC5 was shown to be possibly regulated by hypoxia‐ER stress axis and a potential mechanism for TXNDC5‐driven glioma progression was found to be extracellular matrix (ECM) production which is known to promote tumor aggressiveness. Conclusions Our results uncovered the previously unknown role of TXNDC family members in glioma pathogenesis and showed that TXNDC5 levels could serve as a predictor of clinical outcome and therapy success and may very well be used for targeted therapy.

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ERp46 binds to AdipoR1, but not AdipoR2, and modulates adiponectin signalling

Cited by 59 publications

References 29 publications

Characterisation of the relationship between Heme-oxygenase-1 and adiponectin

Characterisation of the relationship between Heme-oxygenase-1 and adiponectin

Molecular characterisation of the adiponectin receptors, AdipoR1 and AdipoR2

Identification of thioredoxin domain containing family members' expression pattern and prognostic value in diffuse gliomas via in silico analysis

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