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Molecular regulation of anti-inflammatory cytokine receptor in sepsis

Award Number: R01HL136294
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/10/2018
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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Molecular regulation of anti-inflammatory cytokine receptor in sepsis - Abstract Sepsis is the 10th leading cause of death in the US. An unresolved systemic cytokine storm caused by bacterial infection is a hallmark of sepsis. The robust acute inflammatory response, through Toll Like Receptors (TLRs) and interleukin-1R like receptors (ILRs), trigger detrimental effects including multi-organ failure. Despite extensive research, therapies for sepsis focus on the use of antimicrobials that lead to multi-drug resistance. Hence, an unmet scientific need is to understand the molecular regulation of anti-inflammatory responses that diminish the severity of tissue injury. Single immunoglobulin interleukin-1-related receptor (SIGIRR), which is also known as Toll/IL-1 receptor 8, exhibits an anti-inflammatory effect against TLRs and ILRs signaling. Recently, IL-37, which is a suppressor of innate immunity, has been identified as the SIGIRR ligand. Both IL-37 and SIGIRR have been recognized as major therapeutic targets to lessen cytokine storm, however, very little is known regarding the molecular regulation of SIGIRR stability. Receptor degradation, a negative feedback regulation of receptor function, is a highly regulated process by post-translational modification, such as phosphorylation and ubiquitination. Ubiquitination is a molecular signal for protein degradation in either the proteasome or lysosome. De-ubiquitination, which is mediated by deubiquitinating enzymes (DUBs), tightly controls protein stability by removal of ubiquitin chains from target proteins. In our preliminary data, we discovered that (i) SIGIRR is poly-ubiquitinated and degraded in the proteasome in response to its ligand binding; (ii) Ubiquitin-specific protease (USP13), a member of DUBs, targets and stabilizes SIGIRR by hydrolyzing the ubiquitin chains from SIGIRR; (iii) glycogen synthase kinase 3β (GSK3β) phosphorylates SIGIRR and interrupts the association between SIGIRR and USP13, thereby reducing SIGIRR stability; (iv) USP13 increases survival rate in experimental sepsis. These observations have led to the following hypothesis: USP13 ameliorates cytokine storm and septic shock through deubiquitination and stabilization of the anti-inflammatory receptor, SIGIRR. To evaluate this hypothesis we will determine 1) molecular signature of USP13-promoted SIGIRR stability; 2) if GSK3β-induced disruption of USP13/SIGIRR interaction lessens anti-inflammatory effects of SIGIRR; 3) if stabilization of SIGIRR by USP13 mitigates endotoxin-induced pro-inflammatory responses. In summary, this application provides molecular mechanisms by which SIGIRR is degraded via phosphorylation-driven ubiquitination. Our preliminary data has uncovered two previously unrecognized post-translational modifications of SIGIRR: phosphorylation and ubiquitination. Two mediators were revealed: GSK3β, which phosphorylates SIGIRR; and USP13, which de- ubiquitinates SIGIRR. These studies will be the first to elucidate that phosphorylation of SIGIRR promotes its ubiquitination by disassociating USP13 from SIGIRR. These studies will lay the foundation for a significant mechanistic advance regarding the molecular regulation of the inflammatory response through modulation of anti-inflammatory receptor stability.


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: 2024 ( Subtotal = -$449 )
2024	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Lung Diseases Research	000	4	2/7/2024	NON-COMPETING CONTINUATION	-$449
														Subtotal = -$449

Issue Date FY: 2021 ( Subtotal = $419,248 )
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Lung Diseases Research	000	4	1/31/2021	NON-COMPETING CONTINUATION	$377,323
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Lung Diseases Research	001	4	5/18/2021	NON-COMPETING CONTINUATION	$41,925
														Subtotal = $419,248

Issue Date FY: 2020 ( Subtotal = $424,981 )
2020	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Lung Diseases Research	000	3	3/10/2020	NON-COMPETING CONTINUATION	$424,981
														Subtotal = $424,981

Issue Date FY: 2019 ( Subtotal = $481,580 )
2019	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Lung Diseases Research	003	2	4/11/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$356,579
2019	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Lung Diseases Research	001	2	4/10/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$481,580
2019	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	002	1	4/11/2019	NEW	-$356,579
2019	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	1	4/9/2019	NEW	$0
														Subtotal = $481,580

Issue Date FY: 2018 ( Subtotal = $491,628 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Lung Diseases Research	000	1	1/19/2018	NEW	$491,628
														Subtotal = $491,628

Grand Total All Awards = $1,816,988

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Molecular regulation of anti-inflammatory cytokine receptor in sepsis

Award Number: R01HL136294

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/10/2018

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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