PXD030820

PXD030820 is an original dataset announced via ProteomeXchange.

Title	The Inhibitory Receptor Siglec-8 Interacts with FcεRI and Globally Inhibits Intracellular Signaling in Primary Mast Cells Upon Activation
Description	Immunomodulation of mast cell (MC) activity is warranted in allergic and inflammatory diseases where MCs have a central role in pathogenesis. Targeting Siglec-8, an inhibitory receptor on MCs and eosinophils, has shown promising activity in preclinical and clinical studies. While the intracellular pathways that regulate Siglec-8 activity in eosinophils have been well studied, the signaling mechanisms that lead to MC inhibition have not been fully elucidated. Here, we evaluate the intracellular signaling pathways of Siglec‐8‐mediated inhibition in primary MCs using an anti‐Siglec‐8 monoclonal antibody (mAb). Phospho‐proteomic profiling of FcεRI‐activated MCs revealed Siglec-8 mAb-treatment globally inhibited proximal and downstream kinases, leading to attenuated MC activation and degranulation. In fact, Siglec‐8 was found to directly interact with FcεRI signaling molecules. Siglec‐8 inhibition was dependent on both cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that interact with the SH2 containing protein phosphatase Shp-2 upon Siglec-8 phosphorylation. Taken together, these data support a model in which Siglec-8 regulates proximal FcεRI‐induced phosphorylation events through phosphatase recruitment and interaction with FcεRI, resulting in global inhibition of MCs upon Siglec-8 mAb engagement.
HostingRepository	PRIDE
AnnounceDate	2022-01-25
AnnouncementXML	Submission_2022-01-25_05:23:58.465.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Gian Luca Negri
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-01-07 12:50:19	ID requested
⏵ 1	2022-01-25 05:23:58	announced

Dataset with its publication pending

submitter keyword: Siglec-8, mast cell

Brad Youngblood
contact affiliation	Allakos Inc.
contact email	byoungblood@allakos.com
lab head
Gian Luca Negri
contact affiliation	Independent researcher
contact email	negri.gl@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD030820
     1. Label: PRIDE project
     2. Name: The Inhibitory Receptor Siglec-8 Interacts with FcεRI and Globally Inhibits Intracellular Signaling in Primary Mast Cells Upon Activation