Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts

Ishikawa, Yasunobu; Fedeles, Sorin V.; Marlier, Arnaud; Zhang, Chao; Gallagher, Anna-Rachel; Lee, Ann-Hwee; Somlo, Stefan

doi:10.1681/asn.2018060614

Cited by 16 publications

(15 citation statements)

References 72 publications

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“…Consistent with this, ATF6 inhibition also caused enhanced accumulation of MUC1-fs in P cells (Figure S3H). IRE1 inhibition induced apoptosis broadly, in line with its general cytoprotective role (Ishikawa et al, 2019;Lin et al, 2007), with no significant difference between P and N cells (Figure 2B). PERK inhibition had no effect on apoptosis (Figure 2B).…”

Section: Muc1-fs Accumulation Triggers the Atf6 Branch Of The Uprmentioning

confidence: 56%

Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Dvela‐Levitt

Kost‐Alimova

Emani

et al. 2019

Cell

139

129

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Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and reroutes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.(F) IF co-staining of distal tubule in MKD patient kidney organoid for MUC1-wt (red), MUC1-fs (green), E-cadherin (blue), and Na + /K + -ATPase (yellow). MUC1-fs localized intracellularly (middle) compared to apical MUC1-wt (left). (G) IF co-staining in P cells for MUC1-fs (green), MUC1-wt (red), and Hoechst (gray). MUC1-fs localized intracellularly (middle) compared to MUC1-wt on the plasma membrane (left). See also Figures S1, S2, and S3 and Table S1.

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Section: Muc1-fs Accumulation Triggers the Atf6 Branch Of The Uprmentioning

confidence: 56%

Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Dvela‐Levitt

Kost‐Alimova

Emani

et al. 2019

Cell

139

129

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“…XBP1 is an important transcription factor, which is required for ER stress [30]. Published data have manifested that activation of XBP1 may produce an anti-inflammatory effect [31,32]. In this study, XBP1 expression was reduced via upregulation of miR-330-3p.…”

Section: Discussionmentioning

confidence: 53%

Suppression of miR-330-3p alleviates DSS-induced ulcerative colitis and apoptosis by upregulating the endoplasmic reticulum stress components XBP1

Chen

Fang²,

Yao³

et al. 2020

Hereditas

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Background: This study aimed to explore the biological activities of miR-330-3p in dextan sulphate sodium (DSS)induced ulcerative colitis and apoptosis and the direct target of miR-330-3p in this process. HT-29 cells and male C57BL/6 mice were used to examine the function of miR-330-3p in vitro and in vivo, respectively. Expression of miRNA and mRNA was measured using quantitative real time PCR (qRT-PCR). Western blotting was used to measure the change of protein expression. Flow cytometry was used to determine cell apoptosis and luciferase assay was used to confirm the direct target of miR-330-3p. Results: miR-330-3p expression was increased by DSS in both HT-29 cells and mice. Upregulation miR-330-3p induced cell apoptosis, mice weight loss and ulcerative colitis in vivo, which could prevent by suppression of miR-330-3p. Cell apoptosis related protein expression, cleaved caspase-3 and cleaved PARP was also inhibited by miR-330-3p overexpression and elevated by miR-330-3p inhibition both in vitro and in vivo. Luciferase assay confirmed that 3′ untranslated region (3′-UTR) of XBP1 is the directed target of miR-330-3p and Western blotting results have showed that protein expression of XBP1 was decreased by miR-330-3p mimics and increased by miR-330-3p inhibitor. Conclusion: miR-330-3p is upregulated by DSS in both HT-29 cells and mice and promoted ulcerative colitis and cell apoptosis by targeting of 3′-UTR of XBP1, which is a key component of ER stress. Inhibition of miR-330-3p prevent DSS-induced ulcerative colitis and cell apoptosis mediated by upregulation of XBP1 expression.

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“…We and others have previously shown that IRE1α forms a complex with the Sec61 translocon complex (Plumb et al, 2015; Acosta-Alvear et al, 2018; Ishikawa et al, 2019). The complex formation allows IRE1α to access its substrate mRNAs, including XBP1u mRNA, which is delivered to the Sec61 translocon through its ribosome-nascent chain (Plumb et al, 2015; Kanda et al, 2016).…”

Section: Discussionmentioning

confidence: 91%

A Molecular Mechanism for Turning off IRE1α Signaling During Endoplasmic Reticulum Stress

Sun

Appathurai

et al. 2020

Preprint

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20unfolded proteins in the lumen of the endoplasmic reticulum (ER) and propagates the signal to 46 the cytosol. We have previously shown that IRE1α forms a complex with the Sec61 translocon 47 to cleave its substrate mRNAs (Plumb et al., 2015). This complex also regulates IRE1α 48 activation dynamics during ER stress in cells (Sundaram et al., 2017), but the underlying 49 mechanism is unclear. Here, we show that Sec63 is a subunit of the IRE1α/Sec61 translocon 50 complex. Sec63 recruits and activates BiP ATPase through its luminal J-domain to bind onto 51 IRE1α. This Sec63-mediated BiP binding to IRE1α suppresses the formation of higher-order 52 oligomers of IRE1α, leading to proper attenuation of IRE1α RNase activity during persistent ER 53 stress. Thus, our data suggest that the Sec61 translocon bridges IRE1α with Sec63/BiP to 54 regulate the dynamics of IRE1α activity in cells.

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Spliced XBP1 Rescues Renal Interstitial Inflammation Due to Loss of Sec63 in Collecting Ducts

Cited by 16 publications

References 72 publications

Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Suppression of miR-330-3p alleviates DSS-induced ulcerative colitis and apoptosis by upregulating the endoplasmic reticulum stress components XBP1

A Molecular Mechanism for Turning off IRE1α Signaling During Endoplasmic Reticulum Stress

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