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Regulation of Proinflammatory Cytokine Responses by a Caspase-8-N4BP1 Axis

Award Number: DP5OD033360
ORGANIZATION: OFFICE OF THE DIRECTOR, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/13/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Regulation of Proinflammatory Cytokine Responses by a Caspase-8-N4BP1 Axis - Project Summary/Abstract Rare monogenic immune disorders have illuminated key aspects of inflammation, but many of the underlying mechanisms remain poorly understood. For example, autoimmune lymphoproliferative syndrome (ALPS), a disorder in which T cells fail to undergo apoptosis, is most often caused by genetic defects in the death receptor FAS or its ligand FASL. However, mutations in caspase-8 or its adaptor FADD – which mediate cell death downstream of FAS – cause a combination of ALPS plus severe immunodeficiency. Since immunodeficiency is not generally observed in patients with FAS or FASL mutations, I hypothesized that FADD-caspase-8 must have an apoptosis-independent function downstream of an immune receptor other than FAS. Indeed, I recently discovered that activation of multiple immune receptors elicits the caspase-8-mediated cleavage of Nedd4- binding protein 1 (N4BP1), a novel cytokine suppressor. This represents a critical point of regulation during inflammation. Notably, deletion of N4BP1 does not ordinarily affect the TRIF-dependent subset of toll-like receptors (TLRs) that activate caspase-8 (e.g., TLR3 and TLR4). However, the impaired cytokine production of caspase-8-deficient macrophages stimulated with a TLR4 agonist is restored to normal by co-deletion of N4BP1. In contrast, N4BP1 deletion leads to exorbitant cytokine responses by the TRIF-independent TLRs (e.g., TLR1/2, TLR7 and TLR9) that do not directly activate caspase-8. Thus, N4BP1 cleavage by caspase-8 inactivates the anti-inflammatory activity of intact, un-cleaved N4BP1. These findings offer a novel mechanistic explanation for immunodeficiency caused by FADD-caspase-8 mutations, whereby the inability to cleave N4BP1 results in its aberrant persistence and constriction of cytokine responses. Like TLR3 and TLR4 agonists, tumor necrosis factor (TNF) also leads to caspase-8 cleavage of N4BP1, endowing TNF with the ability to inactivate N4BP1 and thereby license cytokine production by the TRIF-independent TLRs. This latter finding highlights a key point of molecular crosstalk between the TNF and TLR systems that converges on caspase-8 cleavage of N4BP1. In the current proposal, I have linked the mechanism by which N4BP1 suppresses cytokine production to a series of proteins with both previously recognized and heretofore unknown roles in inflammation. In Aim 1, I will attempt to decipher the mechanism by which N4BP1 controls the activity of this novel kinase-dependent pathway that suppresses inflammation. In Aim 2, I will dissect how N4BP1 suppresses late phase inflammatory gene expression using genome-scale technologies. In Aim 3, I will explore the mechanisms and in vivo consequences of signal integration by the TNF-caspase-8-N4BP1 axis. Together, these aims will provide novel mechanistic insights explaining a key regulatory circuit underlying inflammation. They also will serve to launch my independent research career.


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: 2026 ( Subtotal = $0 )
2026	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Trans-NIH Research Support	000	3	12/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $885,000 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Trans-NIH Research Support	002	4	8/15/2025	EXTENSION WITH OR WITHOUT FUNDS	$885,000
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Trans-NIH Research Support	000	3	7/22/2025	NON-COMPETING CONTINUATION	$0
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Trans-NIH Research Support	001	3	8/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $885,000

Issue Date FY: 2024 ( Subtotal = $442,500 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Trans-NIH Research Support	000	3	8/14/2024	NON-COMPETING CONTINUATION	$442,500
														Subtotal = $442,500

Issue Date FY: 2023 ( Subtotal = $442,500 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Trans-NIH Research Support	002	2	8/31/2023	NON-COMPETING CONTINUATION	$442,500
2023	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Trans-NIH Research Support	000	1	10/21/2022	NEW	$0
2023	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Trans-NIH Research Support	001	1	1/24/2023	NEW	$0
														Subtotal = $442,500

Issue Date FY: 2022 ( Subtotal = $442,500 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Trans-NIH Research Support	000	1	9/13/2022	NEW	$442,500
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Trans-NIH Research Support	001	1	9/23/2022	NEW	$0
														Subtotal = $442,500

Grand Total All Awards = $2,212,500

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Regulation of Proinflammatory Cytokine Responses by a Caspase-8-N4BP1 Axis

Award Number: DP5OD033360

ORGANIZATION: OFFICE OF THE DIRECTOR, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/13/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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