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PXD048693

PXD048693 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleCRISPR screen for protein inclusion formation uncovers a role for SRRD in the regulation of intermediate filament dynamics and aggresome assembly
DescriptionThe presence of large protein inclusions is a hallmark of neurodegeneration, and yet the precise molecular factors that contribute to their formation remain poorly understood. Screens using aggregation-prone proteins have commonly relied on downstream toxicity as a readout rather than the direct formation of aggregates. Here, we combined a genome-wide CRISPR knockout screen with Pulse Shape Analysis, a FACS-based method for inclusion detection, to identify direct modifiers of TDP-43 aggregation in human cells. Our screen revealed both canonical and novel proteostasis genes, and unearthed SRRD,a poorly characterized protein, as a top regulator of protein inclusion formation. APEX biotin labeling reveals that SRRD resides in proximity to proteins that are involved in the formation and breakage of disulfide bonds and to intermediate filaments, suggesting a role in regulation of the spatial dynamics of the intermediate filament network. Indeed, loss of SRRD results in aberrant intermediatefilament fibrils and the impaired formation of aggresomes, including blunted vimentin cage structure, during proteotoxic stress. Interestingly, SRRD also localizes to aggresomes and unfolded proteins, and rescues proteotoxicity in yeast whereby the its N-terminal low complexity domain is sufficient to induce this affect. Altogether this suggests an unanticipated and broad role for SRRD in cytoskeletal organization and cellular proteostasis.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_06:24:53.918.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterHossein Fazelinia
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListNo PTMs are included in the dataset
InstrumentOrbitrap Exploris 480
Dataset History
RevisionDatetimeStatusChangeLog Entry
02024-01-18 10:43:45ID requested
12024-01-24 08:52:18announced
22024-10-22 06:24:54announced2024-10-22: Updated project metadata.
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: CRISPR, APEX biotin labeling, Aggresome assembly, Cellular proteostasis, Neurodegeneration, Cytoskeletal organization
Contact List
Ophir Shalem, Ph.D.
contact affiliationUniversity of Pennsylvania Department of Genetics 5050 Colket Translational Research Building 3501 Civic Center Boulevard Philadelphia, PA 19104, USA
contact emailshalemo@upenn.edu
lab head
Hossein Fazelinia
contact affiliationChildren's Hospital of Philadelphia
contact emailfazeliniah@email.chop.edu
dataset submitter
Full Dataset Link List
Dataset FTP location
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PRIDE project URI
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