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TAX1BP1 deficiency impair initiation of autophagic flow in HK-2 cells through downregulate AMPK-ULK1 pathway

ABSTRACT: TAX1BP1 deficiency impair initiation of autophagic flow in HK-2 cells through downregulate AMPK-ULK1 pathway

PROVIDER: PRJNA1083895 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28228481_1.fastq.gz	Fastqsanger.gz
	SRR28228481_2.fastq.gz	Fastqsanger.gz
	SRR28228482_1.fastq.gz	Fastqsanger.gz
	SRR28228482_2.fastq.gz	Fastqsanger.gz
	SRR28228483_1.fastq.gz	Fastqsanger.gz

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TAX1BP1 deficiency impair initiation of autophagic flow in HK-2 cells through downregulate AMPK-ULK1 pathway

Project description:Selective autophagy receptor can combine with substrate in cells to degrade them and maintain cellular homeostasis. TAX1BP1, a kind of selective autophagy receptor, has N-terminal SKIP carboxyl homology (SKICH) domain (LC3-Interacting Region) and a C-terminal ubiquitin binding domain (UBD).TAX1BP1 can also be a potential regulatory factor to influence macroautophagy initiation. In order to research the function of TAX1BP1in renal tubular epithelial cells, we knockout and over expressive TAX1BP1 in HK-2 cells and research the state of autophagy flow and senescence. We found that TAX1BP1 knockout could impair initiation of autophagic flow, causing obstruction in LC3 lipidation. Farther, TAX1BP1 knockout could bring senescence and sensitivity in damage factor.

2024-05-01 | GSE260876 | GEO

LncRNA P4HA2-AS1 Drives Renal Interstitial Fibrosis via TRIM32-Mediated K63 Ubiquitination of ULK1 and Autophagic Dysregulation

Project description:Renal interstitial fibrosis (RIF), the central pathological driver of chronic kidney disease (CKD) progression, remains mechanistically incompletely defined. While long non-coding RNAs (lncRNAs) are emerging as critical regulators of CKD, their roles in RIF pathogenesis are poorly understood. Here, we identify the fibrosis-associated lncRNA P4HA2-AS1 as a key modulator of RIF through integrated analyses of unilateral ureteral obstruction (UUO) mice and TGF-β-stimulated human renal tubular epithelial cells (HK-2), combined with RNA sequencing, RNA pull-down, ubiquitination profiling, and autophagic flux assays. P4HA2-AS1 was markedly upregulated in fibrotic kidneys, and its suppression attenuated fibrotic phenotypes in vivo and in vitro while restoring autophagic flux. Mechanistically, P4HA2-AS1 directly binds the E3 ubiquitin ligase TRIM32, impeding its proteasomal degradation. This stabilization enhances TRIM32-mediated K63-linked ubiquitination of ULK1, a master autophagy initiator, leading to aberrant autophagic activation and fibrotic progression. Our study uncovers a previously unrecognized P4HA2-AS1/TRIM32/ULK1 axis that couples dysregulated autophagy to RIF, proposing lncRNA-protein interaction targeting as a therapeutic strategy against renal fibrosis.

2026-01-16 | GSE296844 | GEO

Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo and modulates differential splicing

Project description:Several traumatic and neurodegenerative disorders of the CNS show axonal degeneration as a key and early pathological feature. Following a focal axonal lesion, an extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, activation of autophagic proteins including Unc-51 like autophagy activating kinase 1 (ULK1) has been demonstrated, but its role is incompletely understood. Here, we overexpressed a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons in vitro and in the spinal cord (SC) and optic nerve (ON) in vivo. We found a significant inhibitory effect on autophagy in vitro and in vivo. While no effect on cell survival could be observed, ULK1.DN attenuated AAD after axotomy in microfluidic chambers in vitro. Models of SC injury and ON crush in vivo confirmed an attenuation of axonal degeneration by ULK1.DN. In a translational approach, we employed the selective ULK1 inhibitor SBI-0206965 (SBI) and found an attenuation of AAD after ON crush in vivo mediated by a reduction of autophagy by SBI. Quantitative proteomic profiling after ULK1.DN overexpression in vitro revealed a regulation of proteins associated with translation and splicing. A differential exon expression analysis identified the genes kinesin family member 1B (Kif1b), DNA damage inducible transcript 3 (Ddit3) and WD repeat domain 6 (Wdr6) as targets of ULK1.DN and potential mediators of its degeneration-attenuating effect. These findings reveal ULK1 as an important mediator of axonal degeneration and elucidate its function in splicing, defining it as a putative therapeutic target.

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Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo and modulates differential splicing

Project description:Several traumatic and neurodegenerative disorders of the CNS show axonal degeneration as a key and early pathological feature. Following a focal axonal lesion, an extended axonal disintegration by acute axonal degeneration (AAD) occurs within several hours. During AAD, activation of autophagic proteins, including Unc-51 like autophagy activating kinase 1 (ULK1), has been shown but its role is incompletely understood. Here, we overexpressed a dominant negative of ULK1 (ULK1.DN) in primary rat cortical neurons in vitro and in the spinal cord (SC) and optic nerve (ON) in vivo. We found a significant inhibitory effect on autophagy in vitro and in vivo. While no effect on cell survival could be observed, ULK1.DN attenuated AAD after axotomy in microfluidic chambers in vitro. Models of SC injury and ON crush in vivo confirmed an attenuation of axonal degeneration by ULK1.DN. In a translational approach, we employed the selective ULK1 inhibitor SBI-0206965 (SBI) and found an attenuation of AAD after ON crush in vivo mediated by a reduction of autophagy by SBI. Quantitative proteomic profiling after ULK1.DN overexpression in vitro revealed a regulation of proteins associated with translation and splicing. A differential exon expression analysis then identified the genes kinesin family member 1B (Kif1b), DNA damage inducible transcript 3 (Ddit3) and WD repeat domain 6 (Wdr6) as targets of ULK1.DN and potential mediators of its degeneration-attenuating effect. These findings reveal ULK1 as an important mediator of axonal degeneration and elucidate its function in splicing, defining it as a putative therapeutic target.

2020-04-30 | PXD011862 | Pride

Central Role of ULK1 in Type I Interferon Signaling

Project description:We provide evidence that the Unc-51-like kinase 1 (ULK1) is phosphorylated and activated during engagement of the Type I IFN receptor. Our studies demonstrate that the function of ULK1 controls expression of key interferon stimulated genes (ISGs) that mediate important biological functions, including anti-viral and antineoplastic responses. Total RNA was isolated from untreated and IFNβ-treated Ulk1/2+/+ and Ulk1/2-/- mouse embryonic fibroblasts (MEFs). Cells were treated for 6 hours with or without mouse IFNβ (2500 IU/ml).

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CircFKBP8(5S,6)-encoded protein promotes stress susceptibility in mice by downregulating dopamine D3 receptor expression and its downstream AMPK/mTOR/ULK1 autophagy signalling

Project description:Major depressive disorder (MDD) is a serious mental disorder, yet the mechanism by which circular RNAs (circRNAs) are involved in the pathogenesis of MDD by encoding proteins is unknown. Our previous study found that circFKBP8 (5S, 6) relies on its encoded proteins, namely cFKBP8, to promote susceptibility to chronic unpredictable mild stress (CUMS) in mice, but the precise molecular mechanisms are unknown. Here we found that overexpression of circFKBP8 (5S, 6) or cFKBP8 in neurons of the prelimbic cortex (Prl) of CUMS mice downregulated the expression level of DRD3 and its downstream AMPK/ULK1 (Ser555) and AMPK/mTOR/ULK1 (Ser757) pathways, which resulted in downregulation of neuronal autophagy levels. Interestingly, both activation and overexpression of DRD3 ameliorated the exacerbation of depressive-like behaviors induced by circFKBP8 (5S, 6) or cFKBP8, activated both the AMPK/ULK1 (Ser555) pathway and the AMPK/mTOR/ULK1 (Ser757) pathway, and upregulated neuronal autophagy levels. In conclusion, circFKBP8 (5S, 6) or cFKBP8 promote susceptibility to CUMS in mice, at least in part, by down-regulating DRD3 expression and its downstream AMPK/mTOR/ULK1 signaling pathway-mediated neuronal autophagy.

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LncRNA P4HA2-AS1 Drives Renal Interstitial Fibrosis via TRIM32-Mediated K63 Ubiquitination of ULK1 and Autophagic Dysregulation

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Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo and modulates differential splicing

Project description:Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo and modulates differential splicing

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Transcriptional regulation of genes in AML12 cells treated with Palmitic acid, LXR lingand (GW3965) and Ulk1 siRNA

Project description:Transcriptional regulation of genes in AML12 cells treated with Palmitic acid, LXR lingand (GW3965) and Ulk1 siRNA shows differential effect of Ulk1 KD on LXr responsive genes AML-12 cells co-treated with 0.75mM PA+/- 10ÂµM GW3965 for 24 h +/- Ulk1 SiRNA

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Central Role of ULK1 in Type I Interferon Signaling

2014-08-26 | GSE60778 | GEO