PXD029086

PXD029086 is an original dataset announced via ProteomeXchange.

Title	Proteomic analysis of Marinesco-Sjogren syndrome fibroblasts indicates pro-survival metabolic adaptation to SIL1 loss
Description	Marinesco-Sjogren syndrome (MSS) is a rare multisystem pediatric disorder, caused by loss of function of the endoplasmic reticulum cochaperone SIL1 in about 60% of the patients. SIL1 acts as a nucleotide exchange factor for BiP, which plays a central role in secretory protein folding. SIL1-deficient cells have reduced BiP-assisted protein folding, cannot fulfil their protein needs and experience chronic activation of the unfolded protein response (UPR). Maladaptive UPR may explain the cerebellar and skeletal muscle degeneration re-sponsible for the ataxia and muscle weakness typical of MSS. However, the cause of other, more variable, clinical manifestations, such as mild to severe mental retardation, hypogonadism, short stature and skeletal deformities, are less clear. To gain insights into the pathogenic mechanisms of MSS, we carried out cell bio-logical and proteomic investigations in skin fibroblasts derived from a young patient carrying the SIL1 ... mutation. Despite fibroblasts are not overtly affected in MSS we found morphological and biochemical changes consistent with UPR and metabolic alterations. All the cell machineries involved in RNA splicing and translation were strongly downregulated, while protein degradation via lysosome-based structures was boosted, consistent with an attempt of the cell to reduce the workload of the endoplasmic reticulum and dis-pose misfolded proteins. Cell metabolism was extensively affected as we observed a reduction in lipid syn-thesis, an increase in beta oxidation and an enhancement of the tricarboxylic acid cycle, with upregulation of eight of its enzymes. Finally, the catabolic pathways of various amino acids, including valine, leucine, isoleu-cine, tryptophane, lysine, aspartate and phenylalanine, were enhanced, while the biosynthetic pathways of arginine, serine, glycine and cysteine were reduced. These results indicate profound metabolic alterations in MSS cells in addition to UPR activation and increased protein degradation, which may contribute to make them resistant to SIL1 loss.
HostingRepository	PRIDE
AnnounceDate	2022-02-15
AnnouncementXML	Submission_2022-02-15_10:55:43.954.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Maria Concetta Cufaro
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2021-10-12 08:09:32	ID requested
⏵ 1	2022-02-15 10:55:45	announced

Potenza F, Cufaro MC, Di Biase L, Panella V, Di Campli A, Ruggieri AG, Dufrusine B, Restelli E, Pietrangelo L, Protasi F, Pieragostino D, De Laurenzi V, Federici L, Chiesa R, Sallese M, Proteomic Analysis of Marinesco-Sjogren Syndrome Fibroblasts Indicates Pro-Survival Metabolic Adaptation to SIL1 Loss. Int J Mol Sci, 22(22):(2021) [pubmed]

submitter keyword: Protein folding, unfolded protein response, BiP, pathway analysis, fibroblast, neurodegenerative disease, autophagosome

Piero Del Boccio
contact affiliation	Department Of Pharmacy
contact email	piero.delboccio@unich.it
lab head
Maria Concetta Cufaro
contact affiliation	University "G. d'Annunzio" of Chieti
contact email	maria.cufaro@unich.it
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD029086
     1. Label: PRIDE project
     2. Name: Proteomic analysis of Marinesco-Sjogren syndrome fibroblasts indicates pro-survival metabolic adaptation to SIL1 loss