Dataset Information

MTORC2 interactome and localization determine aggressiveness of high-grade glioma cells through association with gelsolin.

ABSTRACT: The mTOR complex 2 (mTORC2) has been implicated as a key regulator of glioblastoma cell migration. However, the roles of mTORC2 in the migrational control process have not been entirely elucidated. Here we elaborate that mTORC2 is crucial for GBM cell motility. Inhibition of mTORC2 resulted in impaired cell movement, affecting microfilaments and microtubules' functions. Later, we quantitatively characterized the mTORC2 interactome using affinity-purification mass spectrometry (AP-MS) in glioblastoma. We demonstrated that changes in cell migration ability alter mTORC2-associated proteins. These interacting proteins help determine the capability of glioma cell movement.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Brain Glioblastoma Multiforme,Brain Cancer

SUBMITTER: Naphat Chantaravisoot

LAB HEAD: Trairak Pisitkun

PROVIDER: PXD035256 | Pride | 2023-05-10

REPOSITORIES: Pride

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mTORC2 interactome and localization determine aggressiveness of high-grade glioma cells through association with gelsolin.

Chantaravisoot Naphat N Wongkongkathep Piriya P Kalpongnukul Nuttiya N Pacharakullanon Narawit N Kaewsapsak Pornchai P Ariyachet Chaiyaboot C Loo Joseph A JA Tamanoi Fuyuhiko F Pisitkun Trairak T

Scientific reports 20230429 1

mTOR complex 2 (mTORC2) has been implicated as a key regulator of glioblastoma cell migration. However, the roles of mTORC2 in the migrational control process have not been entirely elucidated. Here, we elaborate that active mTORC2 is crucial for GBM cell motility. Inhibition of mTORC2 impaired cell movement and negatively affected microfilament and microtubule functions. We also aimed to characterize important players involved in the regulation of cell migration and other mTORC2-mediated cellul ...[more]

PMID: 37120454

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Project description:The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we describe 43 affected individuals from 27 unrelated families with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (21 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (97%), facial dysmorphism (94%), movement disorders (94%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (74%), oculomotor (68%) and behavioural abnormalities (63%), weight gain (59%), microcephaly (38%) and epilepsy (37%). The most conspicuous and common movement disorder was dystonia (90%), frequently leading to early-onset progressive postural deformities (93%), limb dystonia (40%), and cervical dystonia (25%). A jerky tremor in the upper limbs (61%), a mild head tremor (56%), parkinsonism/hypokinesia developing with advancing age (31%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (66.6%), hypoplasia/agenesis of the anterior commissure (62.9%), short midbrain and small inferior cerebellar vermis (40.7% each), hypertrophy of the clava (18.5%) were common neuroimaging findings. Acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied with developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus models, including of FUS, MARCKS and CHCHD-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders.

			Action	DRS
	AZDF1R1.mgf	Mgf
	AZDF1R1.raw	Raw
	AZDF1R2.mgf	Mgf
	AZDF1R2.raw	Raw
	AZDF1R3.mgf	Mgf