The Bcl‐2 family protein bid interacts with the <scp>ER</scp> stress sensor <scp>IRE1</scp> to differentially modulate its <scp>RNase</scp> activity

Bashir, Samirul; Banday, Mariam; Qadri, Ozaira; Pal, Debnath; Bashir, Aadil; Hilal, Nazia; Altaf, Mohammad; Fazili, Khalid Majid

doi:10.1002/1873-3468.14593

Cited by 4 publications

(2 citation statements)

References 35 publications

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“…Several cytosolic inhibitors, positive modulators, and post-translational modifiers of IRE1α have been identified. While Bax inhibitor-1 (TMBIM6) [49], fortilin [50], and BID [51] were identified as inhibitors, the BCL-2 family members BAX and BAK [52] can act as positive modulators. Moreover, it has been shown that the stability and activity of IRE1α can be modified by post-translational modifications like phosphorylation [53] or ADP-ribosylation [54].…”

Section: Discussionmentioning

confidence: 99%

TurboID-Based IRE1 Interactome Reveals Participants of the Endoplasmic Reticulum-Associated Protein Degradation Machinery in the Human Mast Cell Leukemia Cell Line HMC-1.2

Ahmed,

Preisinger,

Wilhelm

et al. 2024

Cells

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The unfolded protein response is an intricate system of sensor proteins in the endoplasmic reticulum (ER) that recognizes misfolded proteins and transmits information via transcription factors to either regain proteostasis or, depending on the severity, to induce apoptosis. The main transmembrane sensor is IRE1α, which contains cytoplasmic kinase and RNase domains relevant for its activation and the mRNA splicing of the transcription factor XBP1. Mast cell leukemia (MCL) is a severe form of systemic mastocytosis. The inhibition of IRE1α in the MCL cell line HMC-1.2 has anti-proliferative and pro-apoptotic effects, motivating us to elucidate the IRE1α interactors/regulators in HMC-1.2 cells. Therefore, the TurboID proximity labeling technique combined with MS analysis was applied. Gene Ontology and pathway enrichment analyses revealed that the majority of the enriched proteins are involved in vesicle-mediated transport, protein stabilization, and ubiquitin-dependent ER-associated protein degradation pathways. In particular, the AAA ATPase VCP and the oncoprotein MTDH as IRE1α-interacting proteins caught our interest for further analyses. The pharmacological inhibition of VCP activity resulted in the increased stability of IRE1α and MTDH as well as the activation of IRE1α. The interaction of VCP with both IRE1α and MTDH was dependent on ubiquitination. Moreover, MTDH stability was reduced in IRE1α-knockout cells. Hence, pharmacological manipulation of IRE1α–MTDH–VCP complex(es) might enable the treatment of MCL.

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Section: Discussionmentioning

confidence: 99%

TurboID-Based IRE1 Interactome Reveals Participants of the Endoplasmic Reticulum-Associated Protein Degradation Machinery in the Human Mast Cell Leukemia Cell Line HMC-1.2

Ahmed,

Preisinger,

Wilhelm

et al. 2024

Cells

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“…All these proteins help in amplifying the IRE1 signal during ER stress. Other proteins like Fortilin (Pinkaew et al, 2017), Bax inhibitor-1 (Lisbona et al, 2009), and Bid (Bashir et al, 2023) interact with IRE1 to inhibit its activity, while interaction with Nck, TNFR-associated factor 2 (TRAF2) (Luo et al, 2008;Nguyen et al, 2004), and RACK1 (Qiu et al, 2010) form the scaffolding interactions. Besides these physical interactions, IRE1 communicates with other cellular pathways, including the Akt/mTOR signalling pathway (Ozcan et al 2004, Qin et al, 2010, Wouters et al, 2008.…”

Section: Introductionmentioning

confidence: 99%

sMEK1 promotes crosstalk between IRE1 and Akt signalling pathways: Evidence for a novel IRE1/sMEK1/Akt complex

Qadri

Bashir

Banday

et al. 2021

Preprint

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ER is facilitated with a dynamic cellular pathway namely Unfolded Protein Response (UPR): an adaptive signalling mechanism that maintains proteostasis in response to ER stress. IRE1 is one of the three transmembrane sensors of UPR with dual protein kinase and ribonuclease activities. IRE1 acts as a central molecule of UPR, which associates with a number of proteins that either regulate its activity or connect it to other pathways. Here, we report sMEK1 and Akt as novel interacting partners of IRE1 which associate to orchestrate the IRE1 and Akt signalling networks. Our study revealed that ER stress negatively regulates Akt through IRE1 protein. We found that IRE1/sMEK1/Akt form a ternary complex, which results in the dephosphorylation of Akt by protein phosphotase sMEK1 in presence of activated IRE1. Together, this study highlights the UPR/Akt link by delineating the molecular mechanism along with giving insights into the overall impact of this interaction.

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Tumour suppressor protein sMEK1 links to IRE1 signalling pathway to modulate its activity during ER stress

Qadri,

Bashir,

Banday

et al. 2024

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The Bcl‐2 family protein bid interacts with the ER stress sensor IRE1 to differentially modulate its RNase activity

Cited by 4 publications

References 35 publications

TurboID-Based IRE1 Interactome Reveals Participants of the Endoplasmic Reticulum-Associated Protein Degradation Machinery in the Human Mast Cell Leukemia Cell Line HMC-1.2

TurboID-Based IRE1 Interactome Reveals Participants of the Endoplasmic Reticulum-Associated Protein Degradation Machinery in the Human Mast Cell Leukemia Cell Line HMC-1.2

sMEK1 promotes crosstalk between IRE1 and Akt signalling pathways: Evidence for a novel IRE1/sMEK1/Akt complex

Tumour suppressor protein sMEK1 links to IRE1 signalling pathway to modulate its activity during ER stress

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