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Small molecule inhibition of ubiquitin C-terminal hydrolase L1 alters cell metabolism proteins and exerts anti- or pro-tumorigenic effects contingent upon chemosensitivity status in high grade serous ovarian cancer

ABSTRACT: In the current investigation, we sought to characterize the implications of UCHL1 small molecule inhibition in both chemosensitive and chemoresistant HGSOC cells, generating an unprecedented understanding of the clinically relevant implications of targeting UCHL1.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Ovarian Surface Epithelial Cell

DISEASE(S): Ovarian Serous Carcinoma

SUBMITTER: Nicholas DaSilva

LAB HEAD: Nicole James

PROVIDER: PXD060691 | Pride | 2025-02-26

REPOSITORIES: Pride

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			Action	DRS
	ND_Njames_CD1_072923_02293001.raw	Raw
	ND_Njames_CD2_072923_04560501.raw	Raw
	ND_Njames_CD3_072923_08261201.raw	Raw
	ND_Njames_CD4_072923_10525201.raw	Raw
	ND_Njames_i1_072923_14230101.raw	Raw

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cGMP modulates responses to queen mandibular pheromone in worker honey bees

Project description:Responses to social cues, such as pheromones, can be modified by genotype, physiology, or environmental context. Honey bee queens produce a pheromone (queen mandibular pheromone; QMP) which regulates many aspects of worker bee behavior and physiology. Forager honey bees are less responsive to QMP than young nurse bees engaged in brood care, suggesting that physiological changes associated with behavioral maturation may modulate response to this pheromone. Since cGMP is a major regulator of behavioral maturation in honey bee workers, we examined its role in modulating worker responses to QMP. Treatment with a cGMP analog, 8-Br-cGMP, resulted in significant reductions in both behavioral and physiological responses to QMP in young caged workers. Treatment significantly reduced attraction to QMP (the retinue response) and inhibited the QMP-mediated increase in vitellogenin levels in the fat bodies of worker bees. Genome-wide analysis of brain gene expression patterns demonstrated that cGMP has a larger effect on expression levels than QMP, and that QMP has specific effects in the presence of cGMP, suggesting that some responses to QMP may be dependent on an individual beesM-^R physiological state. Several functional gene categories were significantly differentially expressed, including genes involved in regulating GTPase activity, phototransduction, immunity, and carboxylic acid transmembrane transporter activity. Overall, our data suggest that cGMP-mediated processes play a large role in modulating responses to queen pheromone in honey bees, at the behavioral, physiological and molecular levels.

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Discovery of a potent and selective covalent inhibitor and activity-based probe for UCHL1, with anti-fibrotic activity

Project description:Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme (DUB) that is very highly expressed in human brain. UCHL1 has been proposed as a potential therapeutic target in neurodegeneration, cancer, and liver and lung fibrosis, however bona fide molecular functions of UCHL1 are yet to be elucidated. Herein we characterize a potent and selective inhibitor and activity-based probe (IMP-1710) for UCHL1 based on a covalent inhibitor scaffold, and its application to identify and quantify target proteins in intact human cells. IMP-1710 stereoselectively labels the catalytic cysteine of UCHL1 at low nanomolar concentration, and we show that a previously claimed UCHL1 inhibitor (LDN-57444) fails to engage UCHL1 in cells. We further demonstrate that potent UCHL1 inhibitors selectively block pro-fibrotic responses in a cellular model of idiopathic pulmonary fibrosis (IPF), supporting a potential therapeutic role for UCHL1 inhibition.

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Transcriptional response of P. aeruginosa to fosfomycin tobramycin and FT under aerobic and anaerobic conditions

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Ubiquitin C-terminal hydrolase isozyme L1 (UCHL1) is associated with shelterin complex at interstitial telomeric sites

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Metabolic reprogramming in astrocytes prevents neuronal death through a UCHL1/PFKFB3/H4K8la positive feedback loop

Project description:Astrocytic metabolic reprogramming is an adaptation of metabolic patterns to meet increased energy demands, although the role after spinal cord injury (SCI) remains unclear. Analysis of single-cell RNA sequencing (scRNA-seq) data identified an increase in astrocytic glycolysis, while PFKFB3, a key regulator of glycolytic flux, was significantly upregulated following SCI. Loss of PFKFB3 in astrocytes prohibited neuronal energy supply and enhanced neuronal ferroptosis in vitro and inhibited astrogliosis, expanded neuroinflammation, exacerbated neuronal loss, and hindered functional recovery in vivo after SCI. Mechanistically, deubiquitinase UCHL1 plays a crucial role in stabilizing and enhancing PFKFB3 expression by cleaving K48-linked ubiquitin chains. Genetic deletion of Uchl1 inhibited locomotor recovery after SCI by suppression of PFKFB3-induced glycolytic reprogramming in astrocytes. Furthermore, the UCHL1/PFKFB3 axis increased lactate production, leading to enhanced histone lactylation and subsequent transcription of Uchl1 and several genes related to glycolysis, suggesting a glycolysis/H4K8la/UCHL1 positive feedback loop. These findings help to clarify the role of the UCHL1/PFKFB3/H4K8la loop in modulation of astrocytic metabolic reprogramming and reveal a potential target for treatment of SCI.

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Small-Molecule Activity-Based Probe for Monitoring Ubiquitin 2 C‑Terminal Hydrolase (UCHL1) Activity in Live Cells and Zebrafish 3 Embryos

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