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Inhibition of Virally-Induced TFEB Proteasomal Degradation as a Host-Centric Therapeutic Approach for Coronaviral Infection

ABSTRACT: Inhibition of Virally-Induced TFEB Proteasomal Degradation as a Host-Centric Therapeutic Approach for Coronaviral Infection

PROVIDER: PRJNA1242282 | ENA |

REPOSITORIES: ENA

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	SRR32875748_1.fastq.gz	Fastqsanger.gz
	SRR32875748_2.fastq.gz	Fastqsanger.gz

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Inhibition of Virally-Induced TFEB Proteasomal Degradation as a Host-Centric Therapeutic Approach for Coronaviral Infection

Project description:The endo-lysosomal pathway plays an evolutionarily conserved role in pathogen clearance, and both bacteria and viruses have evolved complex mechanisms to evade this host defense system. Here, we describe a novel aspect of coronaviral infection, whereby the master transcriptional activator of lysosomal homeostasis – TFEB – is targeted for proteasomal-mediated degradation upon viral infection. Through mass spectrometry analysis and an unbiased siRNA screen, we identify that TFEB protein stability is coordinately regulated by the E3 ubiquitin ligase subunit DCAF7 and the PAK2 kinase. In particular, viral infection triggers marked PAK2 activation, which in turn, phosphorylates and primes TFEB for ubiquitin-mediated protein degradation. Deletion of either DCAF7 or PAK2 blocks virally-stimulated TFEB degradation and protects against virally-induced cytopathic effects. We further derive a series of novel small molecules that interfere with the DCAF7-TFEB interaction. These agents inhibit virus-induced TFEB degradation and demonstrate broad anti-viral activities including attenuating SARS-CoV-2 infection in two animal models. Together, these results delineate a virally-triggered pathway that impairs lysosomal homeostasis in the host. Small molecule E3 ubiquitin ligase DCAF7 inhibitors that restore lysosomal function represent a novel class of host-directed, anti-viral therapies useful for current and potentially future coronaviral variants.

2025-06-16 | GSE292982 | GEO

USP7 protects TFEB from proteasome-mediated degradation

Project description:The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy. We identify a distinct nuclear interactome of TFEB, with USP7 emerging as a key post-translational modulator of TFEB. Genetic depletion and inhibition of USP7 reveal its critical role in preserving TFEB stability within both nuclear and cytoplasmic compartments. Specifically, USP7 is identified as the deubiquitinase responsible for removing the K48-linked polyubiquitination signal from TFEB at lysine residues K116, K264, and K274, thereby preventing its proteasomal degradation. Functional assays demonstrate the involvement of USP7 in preserving TFEB-mediated transcriptional responses to nutrient deprivation, while also modulating autophagy flux and lysosome biogenesis. As USP7 is a deubiquitinase that protects TFEB from proteasomal degradation, these findings provide the foundation for therapeutic targeting of the USP7-TFEB axis in conditions characterized by TFEB dysregulation and metabolic abnormalities, particularly in certain cancers.

2024-09-17 | PXD055937 | Pride

 PARG regulates the proteasomal degradation of TARG1

Project description: PARG regulates the proteasomal degradation of TARG1

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TFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex

Project description:Tuberous Sclerosis Complex (TSC) is caused by germline TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and tumors in multiple organs including the brain, heart, lung (lymphangioleiomyomatosis), and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in models of TSC. To determine the impact of TFEB in vivo, we generated two novel mouse models of TSC, resulting in premature death, in which kidney pathology was the primary phenotype. RNA sequencing revealed that lysosomal and proteasomal gene pathways were the most highly upregulated in the TSC2-deficient kidneys. Knockout of TFEB rescued both kidney pathology and overall survival in both models, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, mTORC1 activity, which was elevated in the TSC2 knockout kidneys, was normalized by TFEB knockout. Knockdown of Rheb or treatment of TSC2-deficient cells with Rapamycin paradoxically increases TFEB phosphorylation at the mTORC1-site (S211) and relocalizes TFEB from the nucleus to the cytoplasm via a Rag-dependent mechanism. Accordingly, treatment of TSC2 knockout mice with Rapamycin normalized lysosomal gene expression, similar to TFEB knockout, suggesting that the beneficial effects of Rapamycin in TSC are TFEB-dependent. These results change the view of the mechanisms leading to mTORC1 hyperactivation in TSC and may lead to novel therapeutic avenues for the treatment of TSC.

2023-09-28 | GSE244072 | GEO

TFEB degradation is regulated by an IKK/TrCP2 phosphorylation-ubiquitination cascade

Project description:Untargeted and Targeted analysis of purified and dephosphorylated human TFEB protein after TFEB was enzymatically phosphorylated by IKK2.

2023-10-13 | MSV000093106 | MassIVE

TFEB degradation is regulated by an IKK/TrCP2 phosphorylation-ubiquitination cascade

Project description:IKK/beta-TrCP2 phosphorylation-ubiquitination cascade as a major mechanism that governs TFEB stability independently of other TFEB regulators.

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Expression data from injected mice overexpressing TFEB specifically in liver

Project description:In order to identify the effects of transcription factor EB (TFEB) overexpression on the liver transcriptome, we performed Affymetrix GeneChip hybridization experiments on injected mice overexpressing TFEB specifically in the liver. For the analysis of the injected mice overexpressing TFEB, total RNA was extracted from the liver of three mice. RNA extracted from the liver of 3 not-injected mice was used as a control.

2013-04-20 | E-GEOD-35015 | biostudies-arrayexpress

SUMO-chain-regulated proteasomal degradation timing exemplified in DNA replication initiation

Project description:Similar to ubiquitin, SUMO forms chains, but the identity of SUMO-chain-modified factors and the purpose of this modification remain largely unknown. Here, we identify budding yeast SUMO protease Ulp2, able to disassemble SUMO chains, as a DDK interactor enriched at replication origins that promotes DNA replication initiation. Replication-engaged DDK is SUMOylated on chromatin, becoming a degradation-prone substrate when Ulp2 no longer protects it against SUMO-chain assembly. Specifically, SUMO chains channel DDK for SUMO-targeted ubiquitin ligase Slx5/Slx8-mediated and Cdc48 segregase-assisted proteasomal degradation. Importantly, the SUMOylation-defective ddk-KR mutant rescues inefficient replication onset and MCM activation in cells lacking Ulp2, suggesting that SUMO chains time DDK degradation. Using two unbiased proteomic approaches, we further identify subunits of the MCM helicase and other factors as SUMO-chain-modified degradation-prone substrates of Ulp2 and Slx5/Slx8. We thus propose SUMO-chain-/Ulp2-protease-regulated proteasomal degradation as a mechanism that times the availability of functionally-engaged SUMO-modified protein pools during replication and beyond.

2019-09-10 | GSE113835 | GEO

Profiling gene expression in HeLa cells following TFEB transient transfection

Project description:Total RNA samples from three biological replicates in which TFEB was transiently overexpressed in HeLa cells by transfection using a pcDNA3 vector. As negative control, we used total RNA samples from HeLa cells transfected with an empty pcDNA3 vector. TFEB transfection

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Reprograming of Proteasomal Degradation by Branched Chain Amino Acid Metabolism

Project description:Reprograming of Proteasomal Degradation by Branched Chain Amino Acid Metabolism

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