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An essential role of TRIM21 in inflammasome assembly and autoinflammatory disease.

Award Number: K01AR087011
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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An essential role of TRIM21 in inflammasome assembly and autoinflammatory disease. - PROJECT SUMMARY Inflammasomes are cytoplasmic multiprotein complexes responsible for the maturation and release of the inflammatory cytokines interleukin (IL)-1b and IL-18, as well as a specialized form of cell death called pyroptosis to promote an inflammatory host response. ASC (apoptosis-associated speck-like protein containing a CARD) is the central inflammasome adaptor and is required for inflammasome assembly. Upon inflammasome activation, ASC polymerizes and is released as particles during pyroptosis to propagate inflammasome responses to bystander cells. Mechanistic details about inflammasome assembly are still lacking. Inflammasome activation and assembly are tightly controlled processes, and dysregulated or excessive activity leads to uncontrolled release of IL-1b causing chronic inflammation and autoinflammatory disease. Hence, uncontrolled NLRP3 and Pyrin activity causes cryopyrin-associated periodic syndrome (CAPS) and familial Mediterranean fever (FMF), respectively. Targeting IL-1b only partially alleviates inflammasome-mediated inflammation and disease. Therefore, innovative therapeutic approaches are needed to prevent its release or block pyroptosis, as released polymerized ASC particles propagate and perpetuate inflammation. Precise mechanistic details regulating inflammasome assembly, IL-1b release, and the egress of specks are still lacking. I identified the E3 ubiquitin ligase tripartite motif-containing protein (TRIM) 21 as a new binding partner of the essential inflammasome adaptor ASC. In my preliminary work, I showed that TRIM21 is a novel inflammasome component necessary for its assembly and is present on ASC particles released upon inflammasome activation. To advance research on mechanisms contributing to and aggravating the pathogenesis of autoinflammatory syndromes, I propose to dissect TRIM21-mediated inflammasome regulation and its release on ASC particles, which I expect will provide fundamentally new insights into mechanisms governing IL-1b release. I hypothesize that TRIM21 plays a central role in autoinflammatory disease pathology by interacting with and ubiquitinating ASC, thereby promoting ASC polymerization, inflammasome activation, and ASC particle release that propagate inflammation to bystander cells. Moreover, I hypothesize that circulating ASC/TRIM21 particles in autoimmune disease trigger adaptive immune responses leading to TRIM21 autoantibody production, which opsonizes particles and further amplifies inflammation. In Aim1, I will study the underlying mechanisms of TRIM21-mediated inflammasome regulation in myeloid cells using TRIM21-depleted cell lines and our innovative conditional Trim21 KO mice. I will also characterize and examine the role of ASC/TRIM21 particles released during inflammasome activation in propagating and perpetuating inflammation. In Aim2, I will characterize the role of TRIM21 and ASC/TRIM21 particle release and content in inflammatory responses in preclinical models of autoinflammatory disease, specifically CAPS and FMF.


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 = $115,700 )
2026	2026	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/16/2026	NEW	$115,700
														Subtotal = $115,700

Grand Total All Awards = $115,700

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An essential role of TRIM21 in inflammasome assembly and autoinflammatory disease.

Award Number: K01AR087011

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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