Dataset Information

SINE RNAs trigger noncanonical NLRC4 inflammasome via DDX17

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Monocyte, Cell Culture

SUBMITTER: SHAOBIN WANG

LAB HEAD: Jayakrishna Ambati

PROVIDER: PXD016019 | Pride | 2022-06-09

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Ambati_BAF_SW_2376biotin-Alu-THP1.sf3	Other
	f190703f04.mzid.gz	Mzid
	f190703f04.mzid_f190703f04.MGF	Mzid
	f190703f04.mzid_f190703f04.pride.mgf.gz	Mzid
	f190703f04.pride.mztab.gz	Mztab

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Publications

DDX17 is an essential mediator of sterile NLRC4 inflammasome activation by retrotransposon RNAs.

Wang Shao-Bin SB Narendran Siddharth S Hirahara Shuichiro S Varshney Akhil A Pereira Felipe F Apicella Ivana I Ambati Meenakshi M Ambati Vidya L VL Yerramothu Praveen P Ambati Kameshwari K Nagasaka Yosuke Y Argyle Dionne D Huang Peirong P Baker Kirstie L KL Marion Kenneth M KM Gupta Kartik K Liu Bo B Hinton David R DR Canna Scott W SW Sallam Tamer T Sadda Srinivas R SR Kerur Nagaraj N Gelfand Bradley D BD Ambati Jayakrishna J

Science immunology 20211203 66

Detection of microbial products by multiprotein complexes known as inflammasomes is pivotal to host defense against pathogens. Nucleotide-binding domain leucine-rich repeat (NLR) CARD domain containing 4 (NLRC4) forms an inflammasome in response to bacterial products; this requires their detection by NLR family apoptosis inhibitory proteins (NAIPs), with which NLRC4 physically associates. However, the mechanisms underlying sterile NLRC4 inflammasome activation, which is implicated in chronic non ...[more]

PMID: 34860583

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Project description:Background: Age-related macular degeneration (AMD) is caused by the degeneration of the macular photoreceptors. This is preceded by development of subretinal protein aggregates (drusen) and degeneration of the macular retinal pigment epithelium (RPE). The underlying pathogenesis remains unknown, but the immune system is suspected to play a key role in it. Aging of the immune system, immunosenescence, includes changes in T cell sub-populations and results in low-level chronic inflammation. Because AMD exclusively occurs in patients over 55 years of age, we hypothesize that aging of the T cell compartment may be implicated in AMD pathogenesis. Methodology and principal findings: Using an in vitro co-culture system, we investigated the effects of activated T cells on a human RPE cell line (ARPE-19). Differential gene expression in the RPE cells of complement factor genes was identified using microarrays, and selected gene transcripts from the alternative complement pathway were validated by q-RT-PCR. Protein expression was determined by ELISA and immunoblotting. Co-culture with activated T cells increased RPE mRNA and protein expression of complement component C3, factors B, H, H-like 1, CD46, CD59, and clusterin, in a dose-dependent manner. Conclusions: RPE cells responded to inflammatory assault caused by exposure to T cell-derived cytokines by upregulating expression of many complement factors from the alternative pathway. This may have implications for RPE ability to deal with complement attack, and opsonization and removal of debris from the RPE-choroidal interface. We speculate that regulation of the complement system in response to inflammatory assault may play a vital role in RPE pathology and drusen biogenesis. Experiment Overall Design: 10 samples investigating variations of co-cultures of RPE cells and T-cells. Variable parameters include the cell type, the co-culturing of the counter-part cell type and the orientation of the system (apical vs basolateral).