PXD054648

PXD054648 is an original dataset announced via ProteomeXchange.

Title	Impairment of lipid homeostasis causes lysosomal accumulation of endogenous protein aggregates through ESCRT disruption
Description	Protein aggregation increases during aging and is a pathological hallmark of many age-related diseases. Protein homeostasis (proteostasis) depends on a core network of factors directly influencing protein production, folding, trafficking, and degradation. Cellular proteostasis also depends on the overall composition of the proteome and numerous environmental variables. Modulating this cellular proteostasis state can influence the stability of multiple endogenous proteins, yet the factors contributing to this state remain incompletely characterized. Here, we performed genome-wide CRISPRi screens to elucidate the modulators of proteostasis state in mammalian cells, using a fluorescent dye to monitor endogenous protein aggregation. These screens recovered components of the known proteostasis network, and uncovered a link between protein and lipid homeostasis. We showed that increased lipid uptake and/or disrupted lipid metabolism led to increased lysosomal, detergent-insoluble protein aggregates and, concomitantly, accumulation of sphingomyelins and cholesterol esters. Proteomic analysis of lysosomes revealed ESCRT accumulation at the lysosomes, suggesting disruption of ESCRT disassembly, lysosomal membrane repair, and microautophagy. Lipid dysregulation leads to lysosomal membrane permeabilization, but does not otherwise impact fundamental aspects of lysosomal and proteasomal functions. Together, these results demonstrate that lipid dysregulation impairs proteostasis via ESCRT disruption, potentially as a result of modified membrane properties.
HostingRepository	PRIDE
AnnounceDate	2024-12-20
AnnouncementXML	Submission_2024-12-20_09:18:43.665.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Niclas Olsson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-06 11:29:44	ID requested
⏵ 1	2024-12-20 09:18:44	announced

10.7554/ELIFE.86194.2;

submitter keyword: Human, TMT, lysosomes, proteostasis, Orbitrap

Fiona McAllister
contact affiliation	Calico Life Sciences
contact email	fiona@calicolabs.com
lab head
Niclas Olsson
contact affiliation	Calico Life Sciences
contact email	niclas@calicolabs.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD054648
     1. Label: PRIDE project
     2. Name: Impairment of lipid homeostasis causes lysosomal accumulation of endogenous protein aggregates through ESCRT disruption