PXD078420-1

PXD078420 is an original dataset announced via ProteomeXchange.

Title	TRAILshort disrupts T cell receptor signaling and promotes immune tolerance in vivo
Description	TRAIL is a TNF family ligand that trimerizes upon engaging TRAIL-R1 (DR4) or TRAIL-R2 (DR5) to induce apoptosis, necroptosis, and/or NFκB activation in receptor-bearing cells. We previously identified TRAILshort as a splice variant of TRAIL that lacks cysteine 230, cannot trimerize, and acts as a dominant-negative ligand that blocks TRAIL-mediated apoptosis. TRAILshort is expressed on cell surfaces and within extracellular vesicles, enabling it to confer TRAIL resistance to both producing and bystander cells. Here, we show that elevated TRAILshort levels are associated with chronic viral infections, cancer, and autoimmune diseases, suggesting a link to impaired immune regulation. Using unbiased phosphoproteomics and mechanistic studies, we demonstrate that TRAILshort binding to DR5 recruits and activates the phosphatase SHP-1, leading to ZAP-70 dephosphorylation, disruption of ZAP-70–CD3ζ interactions, and impaired T cell receptor signaling, thereby reducing T cell activation, proliferation, and cytokine production in response to antigen or CD3/CD28 ligation. Genetic or pharmacologic SHP-1 inhibition reverses these effects. In humanized mouse models, TRAILshort promotes persistence of transformed MEFs and L428 Hodgkin lymphoma and antagonizes CD19 CAR T cell activity, revealing TRAILshort as an immunosuppressive modulator of T cell function with potential therapeutic implications in TRAILshort-high diseases.
HostingRepository	PRIDE
AnnounceDate	2026-05-20
AnnouncementXML	Submission_2026-05-20_11:48:19.460.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dong-Gi Mun
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Eclipse; Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2026-05-15 15:38:19	ID requested
⏵ 1	2026-05-20 11:48:19	announced

Dataset with its publication pending

submitter keyword: Immune tolerance, T cell receptor,TRAILshort

Akhilesh Pandey
contact affiliation	Department of Laboratory Medicine and Pathology, Mayo Clinic, USA
contact email	pandey.akhilesh@mayo.edu
lab head
Dong-Gi Mun
contact affiliation	Mayo Clinic
contact email	mun.dong-gi@mayo.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD078420
     1. Label: PRIDE project
     2. Name: TRAILshort disrupts T cell receptor signaling and promotes immune tolerance in vivo