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NLRP3 inflammasome activation and its crosstalk with RLR signaling at the mitochondria

Award Number: R01AI163131
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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NLRP3 inflammasome activation and its crosstalk with RLR signaling at the mitochondria - Project Summary NLRP3 (NOD-Like Receptor Protein 3) is an intracellular sensor that detects a variety of stimuli including infection and metabolic dysfunction resulting in assembly of a macromolecular signaling complex called the inflammasome which promotes caspase-1 dependent processing of the cytokines IL-1b and IL-18 to their bioactive forms; these cytokines in turn underlie the pathophysiology of many autoinflammatory, autoimmune, metabolic and infectious diseases. NLRP3 is activated by a wide-range of molecules including monosodium urate crystals, viral RNA and even bacterial pore-forming toxins, but little is known about the mechanisms by which NLRP3 senses and elicits a response to these chemically and structurally dissimilar stimuli. We and others have previously shown that NLRP3 associates with mitochondria upon activation. Whether this link simply points to a requirement for a membrane platform to achieve efficient solid-phase assembly of inflammasome signaling components or an active modulation of NLRP3 activation by mitochondrial components or even mitochondrial proteins remains ambiguous. It is also unclear if and how interaction of NLRP3 with mitochondria influences mitochondrial functions. We have previously shown that NLRP3 mitochondrial recruitment and the ensuing inflammasome response is dependent on interaction of a short N- terminal sequence in NLRP3 with the outer mitochondrial adapter protein MAVS. However, MAVS specifically augments inflammasome assembly in response to non-crystalline, but not crystalline NLRP3 activators suggesting an interesting and complex mechanism by which mitochondria regulate NLRP3 inflammasome activation. In this study, we propose that additional mitochondrial proteins control NLRP3 inflammasome activation in response to different activators, conceivably in a stimulus-specific manner. In response to detection of RNA viruses MAVS is engaged not only by NLRP3 but also by the RIG-I- like receptors (RLRs) to produce type 1 interferons, suggesting an unexpected crosstalk between the NLRP3 and RLR signaling pathways. In this proposal, we will elucidate the mechanisms by which mitochondria/MAVS regulate NLRP3 activation and examine its crosstalk with the RLR pathway. This will be accomplished by: 1) mass spectrometry to identify additional mitochondrial proteins that associate with inflammasome complexes in response to crystals and non-crystalline NLRP3 activators, followed by assays to evaluate their effect on inflammasome activation and mitochondrial functions, 2) soft X-ray tomography and correlative fluorescence microscopy to assess a requirement for subcellular membrane platforms in inflammasome assembly, and 3) models of viral infection to identify the physiological consequences of MAVS-dependent crosstalk between the NLRP3 and RLR pathways. These investigations will yield important mechanistic insights into how mitochondria and MAVS regulate NLRP3 inflammasome activation, which may be of relevance for modulation of NLRP3 activity not only in viral infections but also in a variety of metabolic diseases.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $470,000 )
2025	2025	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	5	5/28/2025	NON-COMPETING CONTINUATION	$470,000
														Subtotal = $470,000

Issue Date FY: 2024 ( Subtotal = $470,000 )
2024	2024	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	4	5/14/2024	NON-COMPETING CONTINUATION	$470,000
														Subtotal = $470,000

Issue Date FY: 2023 ( Subtotal = $457,500 )
2023	2023	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	3	5/16/2023	NON-COMPETING CONTINUATION	$0
2023	2023	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	3	5/2/2023	NON-COMPETING CONTINUATION	$457,500
														Subtotal = $457,500

Issue Date FY: 2022 ( Subtotal = $457,500 )
2022	2022	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	5/23/2022	NON-COMPETING CONTINUATION	$457,500
														Subtotal = $457,500

Issue Date FY: 2021 ( Subtotal = $457,500 )
2021	2021	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	6/15/2021	NEW	$457,500
														Subtotal = $457,500

Grand Total All Awards = $2,312,500

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NLRP3 inflammasome activation and its crosstalk with RLR signaling at the mitochondria

Award Number: R01AI163131

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/15/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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