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Ovarian Tumor Deubiquitinase 1, Aberrant Epithelial Cells and Lung Fibrosis

Award Number: R01HL185349
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Ovarian Tumor Deubiquitinase 1, Aberrant Epithelial Cells and Lung Fibrosis - PROJECT SUMMARY Aberrant differentiation of epithelial cells accompanies a number of chronic lung diseases including COPD, lung cancer and idiopathic pulmonary fibrosis (IPF). Notably, the aberrant persistence of high keratin 8-expressing (KRT8high) transitional epithelial cells that fail to differentiate into alveolar type 1 (AT1 cells) has emerged as a contributory process in IPF pathogenesis. The cytokine, interleukin-1 (IL1B) induces reprogramming of alveolar type 2 epithelial cells (AT2) cells to KRT8high transitional cells that give rise to AT1 cells. However, sustained IL1B signaling stalls transitional cells. We recently showed that increases in protein glutathione-conjugation (PSSG) increases the responsiveness of lung epithelial cells to IL1B and identified ovarian tumor deubiquitinase 1 (OTUB1) as a target of IL1B-induced PSSG. The functional role of OTUB1 in IPF pathogenesis remains unclear. OTUB1 functions in multiple ways; it’s canonical deubiquitinase (DUB) action removes lysine 48-linked ubiquitin (K48-Ub) chains to prevent substrate degradation. OTUB1 also can act non-canonically by binding to E2 ubiquitin-conjugating enzymes (E2-UBE): The latter mode inhibits its DUB activity and prevents transfer of Ub from the E2-UBE to E3 ligases. We discovered that OTUB1-SSG, notably at cysteine 23 (OTUB1-C23-SSG) augments its non-canonical function and hypothesize this destabilizes the E3 ligase, NEDD4 Like E3 Ubiquitin Protein Ligase (NEDD4L) in turn leading to the prolonged activity of mammalian target of rapamycin (MTOR) to promote the persistent KRT8high state and fibrosis. New preliminary data show that glutathione S-transferase P (GSTP) is highly expressed in KRT8high epithelial cells in patients with IPF and that GSTP catalyzes OTUB1- SSG. We also discovered that a new covalent chemical modifier of OTUB1-C23, EN523, attenuates OTUB1- SSG, increases NEDD4L and decreases MTOR and KRT8 expression. These collective observations led us to hypothesize that GSTP-catalyzed glutathionylation of OTUB1 at Cys23 (OTUB1-C23-SSG) promotes the aberrant persistence of KRT8high transitional cells by disabling NEDD4L-mediated ubiquitination of MTOR leading to impaired differentiation into mature AT1 cells. In Specific Aim 1 we will determine the functional importance of GSTP in promoting OTUB1-SSG, the persistence of transitional cells and aberrant alveolar repair. In Specific Aim 2 we will address the role of OTUB1-C23-SSG in causing the persistence of the KRT8high epithelial cells and aberrant alveolar repair. In Specific Aim 3 we will elucidate the role of OTUB1-C23-SSG in interfering with NEDD4L-mediated ubiquitin conjugation leading to the prolonged activity of MTOR. Our Aims incorporate the use of a covalent molecule that targets OTUB1-Cys23, a GSTP inhibitor that has been used clinically, as well as organoids and PCLS derived from IPF patients. Completion of this proposal not only will yield new mechanistic insights into the biochemical pathways and post-translational modifications that lead to stalling of KRT8high cells, but also provides translational approaches aimed at promoting alveolar repair.


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 = $753,907 )
2026	2026	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	1	7/10/2026	NEW	$753,907
														Subtotal = $753,907

Grand Total All Awards = $753,907

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Ovarian Tumor Deubiquitinase 1, Aberrant Epithelial Cells and Lung Fibrosis

Award Number: R01HL185349

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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