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Convergent Activation of the Integrated Stress Response and ER–Mitochondria Uncoupling in VAPB-Associated ALS

ABSTRACT: Human iPSC-derived motor neurons with either VAPB WT or VAPB P56S expressed under the control of a doxycycline inducible promoter were grown out to day 35 of motor neuron differentiation. A co-immunoprecipitation was then performed using the VAPB protein as bait to determine the interactome of VAPB and the effect of the P56S mutation upon it, specifically within motor neurons, the affected cell type in ALS.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Motor Neuron

DISEASE(S): Amyotrophic Lateral Sclerosis Type 1

SUBMITTER: Belinda Willard

LAB HEAD: Helen Miranda

PROVIDER: PXD065524 | Pride | 2025-09-15

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	IP_KO.msf	Msf
	IP_KO.mzML	Mzml
	IP_KO.mzid	Mzid
	IP_KO.raw	Raw
	IP_OS.msf	Msf

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1 - 5 of 30

Publications

Convergent activation of the integrated stress response and ER-mitochondria uncoupling in VAPB-associated ALS.

Landry Curran C Costanzo James P JP Mitne-Neto Miguel M Zatz Mayana M Schaffer Ashleigh E AE Hatzoglou Maria M Muotri Alysson R AR Miranda Helen C HC

EMBO molecular medicine 20250805 9

Vesicle-associated membrane protein-associated protein-B (VAPB) is an endoplasmic reticulum (ER) membrane-bound protein. The P56S mutation in VAPB causes a dominant, familial form of amyotrophic lateral sclerosis (ALS). However, the mechanism by which this mutation leads to motor neuron (MN) degeneration remains unclear. Utilizing inducible pluripotent stem cell (iPSC)-derived MNs expressing either wild-type (WT) or P56S VAPB, we demonstrate that the mutant protein reduces neuronal firing and di ...[more]

PMID: 40764463

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2018-08-21 | PXD010178 | Pride

VAPB interacts with phosphorylated ELYS at decondensing chromosomes during mitosis - phosphorylation analysis

Project description:ELYS is a nucleoporin that localizes to the nuclear side of the nuclear envelope in interphase cells. In mitosis, it serves as an assembly platform that interacts with chromatin and then with nucleoporin subcomplexes to initiate the formation of novel nuclear pore complexes. Here we describe the interaction of ELYS with the membrane protein VAPB. In mitosis, ELYS becomes phosphorylated at many sites, including a predicted FFAT (two phenylalanines in an acidic tract) motif, which is shown to mediate interaction with the MSP (major sperm protein)-domain of VAPB. Phosphorylation-dependent binding of VAPB to ELYS is demonstrated by peptide binding assays and co-immunoprecipitation experiments. In anaphase, the two proteins co-localize to the non-core region of the newly forming nuclear envelope. Depletion of VAPB resulted in prolonged mitosis and slow progression from meta- to anaphase and also to chromosome segregation defects. Together, our results suggest an active role of VAPB in recruiting membrane fragments to chromatin and in the biogenesis of a novel nuclear envelope during mitosis.

2024-04-17 | PXD048054 | Pride

VAPB interacts with phosphorylated ELYS at decondensing chromosomes during mitosis (AP-MS Data)

Project description:ELYS is a nucleoporin that localizes to the nuclear side of the nuclear pore complex (NPC) in interphase cells. In mitosis, it serves as an assembly platform that interacts with chromatin and then with nucleoporin subcomplexes to initiate post-mitotic NPC assembly. Here we identified and characterized ELYS as a major binding partner of the membrane protein VAPB during mitosis. In mitosis, ELYS becomes phosphorylated at many sites, including a predicted FFAT (two phenylalanines in an acidic tract) motif, which is shown to mediate interaction with the MSP (major sperm protein)-domain of VAPB. Phosphorylation-dependent binding of VAPB to ELYS is demonstrated by peptide binding assays and co-immunoprecipitation experiments. In anaphase, the two proteins co-localize to the non-core region of the newly forming nuclear envelope. Depletion of VAPB resulted in prolonged mitosis and slow progression from meta- to anaphase and also to chromosome segregation defects. Together, our results suggest a role of ELYS-VAPB-complexes in recruiting membrane fragments to chromatin.

2024-04-12 | PXD047720 | Pride

MS2-affinity purification coupled with RNAseq (MAPS) revealed functional tRNA-derived RNA fragments

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-04-16 | E-GEOD-66520 | biostudies-arrayexpress

VAPB regulates proliferation in medulloblastoma

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Transcription profiling by array of Pseudomonas aeruginosa PA14 cbrA deletion mutant and P14 parent strain

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2011-01-30 | E-FPMI-22 | biostudies-arrayexpress

Stay or Go: Sulfolobales Biofilm Dispersal is Dependent on a Bifunctional VapB Antitoxin

Project description:A Type II VapB14 Antitoxin regulates biofilm dispersal in the archaeal thermoacidophile Sulfolobus acidocaldarius, not only through traditional Toxin neutralization but also through noncanonical transcriptional regulation. Type II VapC Toxins are ribonucleases that are neutralized by their proteinaceous cognate Type II VapB Antitoxin. VapB Antitoxins have a flexible tail at their C-terminus that covers the Toxin’s active site neutralizing its activity. VapB Antitoxins also have a DNA binding domain at their N-terminus that allows them to not only auto-repress their own promoters but also distal targets. VapB14 Antitoxin gene deletion in S. acidocaldarius stunted biofilm and planktonic growth and increased motility structures (archaella). Conversely, planktonic cells were devoid of archaella in the ΔvapC14 cognate Toxin mutant. VapB14 is highly conserved at both the nucleotide and amino acid levels across the Sulfolobales, extremely unusual for Type II Antitoxins that are typically acquired through horizontal gene transfer. Furthermore, homologs of VapB14 are found across the Crenarchaeota, in some Euryarchaeota, and even bacteria. S. acidocaldarius vapB14 and its homolog in the thermoacidophile Metallosphaera sedula (Msed_0871) were both up-regulated in biofilm cells, supporting the role of the Antitoxin in biofilm regulation. The findings here suggest that a stand-alone VapB-type Antitoxin was the product of selective evolutionary pressure to influence biofilm formation in these archaea, a vital microbial community behavior.

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Mechanism of chaperone coordination during cotranslational protein folding in bacteria

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2024-07-03 | PXD048623 | Pride

Systemwide effects of ER-intracellular membrane contact site disturbance in primary endothelial cells

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MS2-affinity purification coupled with RNA sequencing (MAPS) reveals RyhB sRNA targetome

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