PXD016019

PXD016019 is an original dataset announced via ProteomeXchange.

Title	SINE RNAs trigger noncanonical NLRC4 inflammasome via DDX17
Description	Short interspersed element (SINE) RNAs are upregulated by cellular stresses1 (heat shock, DNA damage and viral infection) and accumulate in human diseases (macular degeneration2, lupus3, and Alzheimer’s disease4). These transcripts activate inflammasomes5, a family of cytoplasmic multiprotein complexes that sense danger molecules and initiate innate immune responses by activating caspase-1-dependent cytokine production and inflammatory death6, but the molecular sensor of SINE RNAs is unknown. Here, we identify DDX17, a member of the DEAD box family of RNA helicases7, as a sensor of SINE RNAs requisite for inflammasome activation. Induction of caspase-1 cleavage and release of IL-1 and IL-18 by SINE RNAs requires dual recruitment of NLRP3 and NLRC4 but proceeds independent of NAIPs, immune sensors required for canonical NLRC4 activation by bacterial proteins8,9. Instead, SINE RNAs trigger DDX17–NLRC4 interaction, which licenses inflammasome activation. We also report increased levels of DDX17 protein and association of DDX17 and NLRC4 in the retinal pigmented epithelium (RPE) of human eyes with an advanced, untreatable form of age-related macular degeneration (AMD). Disrupting DDX17–NLRC4 signalling blocks SINE RNA-induced inflammasome activation in human RPE cells and RPE degeneration in an animal model of AMD. Our findings uncover a non-canonical mode of inflammasome activation by endogenous retrotransposon transcripts, and provide new potential targets for macular degeneration and potentially other diseases.
HostingRepository	PRIDE
AnnounceDate	2022-06-09
AnnouncementXML	Submission_2022-06-09_02:02:34.873.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD016019
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	SHAOBIN WANG
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Oxidation; Carbamidomethyl
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-10-25 02:34:55	ID requested
⏵ 1	2022-06-09 02:02:38	announced

Wang SB, Narendran S, Hirahara S, Varshney A, Pereira F, Apicella I, Ambati M, Ambati VL, Yerramothu P, Ambati K, Nagasaka Y, Argyle D, Huang P, Baker KL, Marion KM, Gupta K, Liu B, Hinton DR, Canna SW, Sallam T, Sadda SR, Kerur N, Gelfand BD, Ambati J, DDX17 is an essential mediator of sterile NLRC4 inflammasome activation by retrotransposon RNAs. Sci Immunol, 6(66):eabi4493(2021) [pubmed]

submitter keyword: Inflammasome, DDX17, SINE, AMD

Jayakrishna Ambati
contact affiliation	1Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, Virginia, USA
contact email	ja9qr@virginia.edu
lab head
SHAOBIN WANG
contact affiliation	The University of Virginia
contact email	sw3ta@virginia.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD016019
     1. Label: PRIDE project
     2. Name: SINE RNAs trigger noncanonical NLRC4 inflammasome via DDX17