PXD035128

PXD035128 is an original dataset announced via ProteomeXchange.

Title	Reduced endosomal microautophagy activity in aging associates with enhanced exocyst-mediated protein secretion
Description	Autophagy is essential for protein quality control and regulation of the functional proteome. Failure of autophagy pathways with age contributes to loss of proteostasis in aged organisms and accelerates progression of age-related diseases. In this work, we show that activity of endosomal microautophagy (eMI), a selective type of autophagy occurring in late endosomes, declines with age and identify the subproteome affected by this loss of function. Proteomics of late endosomes from old mice revealed an aberrant glycation signature for hsc70, the chaperone responsible for substrate targeting to eMI. Age-related hsc70 glycation reduces its stability in late endosomes by favoring its organization into high molecular weight protein complexes and promoting its internalization/degradation inside late endosomes. Reduction of eMI with age associates with an increase in protein secretion, as late endosomes can release protein-loaded exosomes upon plasma membrane fusion. Our search for molecular mediators of the eMI/secretion switch identified the exocyst-RalA complex, known for its role in exocytosis, as a novel physiological eMI inhibitor that interacts with hsc70 and acts directly at the late endosome membrane. This inhibitory function along with the higher exocyst-RalA complex levels detected in late endosomes from old mice could explain, at least in part, reduced eMI activity with age. Interaction of hsc70 with components of the exocyst-RalA complex places this chaperone in the switch from eMI to secretion. Reduced intracellular degradation in favor of extracellular release of undegraded material with age may be relevant to the spreading of proteotoxicity associated with aging and progression of proteinopathies.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:28:25.698.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alicia Richards
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-07-06 14:41:50	ID requested
1	2023-03-10 19:10:43	announced
⏵ 2	2023-11-14 08:28:27	announced	2023-11-14: Updated project metadata.

Krause GJ, Diaz A, Jafari M, Khawaja RR, Agullo-Pascual E, Santiago-Fern, á, ndez O, Richards AL, Chen KH, Dmitriev P, Sun Y, See SK, Abdelmohsen K, Mazan-Mamczarz K, Krogan NJ, Gorospe M, Swaney DL, Sidoli S, Bravo-Cordero JJ, Kampmann M, Cuervo AM, Reduced endosomal microautophagy activity in aging associates with enhanced exocyst-mediated protein secretion. Aging Cell, 21(10):e13713(2022) [pubmed]

submitter keyword: autophagy, chaperones,aging, proteostasis, LC-MS/MS

Danielle Swaney
contact affiliation	Department of Cellular Molecular Pharmacology, University of California San Francisco, 1700 4th Street, San Francisco, CA 94158
contact email	danielle.swaney@ucsf.edu
lab head
Alicia Richards
contact affiliation	Krogan lab
contact email	alicia.richards@ucsf.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/03/PXD035128

PRIDE project URI

• PRIDE
  1. PXD035128
     1. Label: PRIDE project
     2. Name: Reduced endosomal microautophagy activity in aging associates with enhanced exocyst-mediated protein secretion