Lkb1 interacts with a ciliopathy complex to regulate inflammation
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ABSTRACT:
PROVIDER: PRJNA339988 | ENA |
REPOSITORIES: ENA
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Project description:Ciliopathies comprise a spectrum of inherited disorders involving different organ systems such as the central nervous system, the skeleton, and the kidney1. The cilium is a hair-like organelle at the cell surface that acts as a sensor and signal transducer2. Many ciliopathy manifestations can be linked to deficient cilia function, yet it is unclear how a cilium defect results in nephronophthisis (NPHP), the most prevalent renal manifestation in children, characterized by inflammation, interstitial fibrosis, and renal cysts3. Here, we report that deletion of the serine threonine kinase Lkb1 in the mouse kidney results in cardinal features of nephronophthisis. An in-vivo proteomic interaction screen revealed ANKS3, a known interaction partner of the nephronophthisis protein NPHP1, and its interactor NEK7 as novel binding partners of LKB1. Lkb1 genetically interacts with Nphp1 in zebrafish. Unbiased transcriptional analysis in-vitro and in-vivo revealed that the chemokine CCL2 is upregulated in Lkb1 deficiency and is accompanied by recruitment of CCR2 expressing mononuclear cells in the kidney. CCL2 regulation requires NPHP1, ANKS3 and NEK7. These findings link LKB1 and ciliopathy proteins to immune regulation and explain how mutations in NPHP proteins result in fibrosis of the kidney.
2018-06-10 | GSE86009 | GEO
Project description:Ciliopathies comprise a spectrum of inherited disorders involving different organ systems such as the central nervous system, the skeleton, and the kidney1. The cilium is a hair-like organelle at the cell surface that acts as a sensor and signal transducer2. Many ciliopathy manifestations can be linked to deficient cilia function, yet it is unclear how a cilium defect results in nephronophthisis (NPHP), the most prevalent renal manifestation in children, characterized by inflammation, interstitial fibrosis, and renal cysts3. Here, we report that deletion of the serine threonine kinase Lkb1 in the mouse kidney results in cardinal features of nephronophthisis. An in-vivo proteomic interaction screen revealed ANKS3, a known interaction partner of the nephronophthisis protein NPHP1, and its interactor NEK7 as novel binding partners of LKB1. Lkb1 genetically interacts with Nphp1 in zebrafish. Unbiased transcriptional analysis in-vitro and in-vivo revealed that the chemokine CCL2 is upregulated in Lkb1 deficiency and is accompanied by recruitment of CCR2 expressing mononuclear cells in the kidney. CCL2 regulation requires NPHP1, ANKS3 and NEK7. These findings link LKB1 and ciliopathy proteins to immune regulation and explain how mutations in NPHP proteins result in fibrosis of the kidney.
2018-06-10 | GSE86010 | GEO
Project description:Lkb1 interacts with a ciliopathy complex to regulate inflammation (array)
| PRJNA339996 | ENA
Project description:Lkb1 interacts with a ciliopathy complex to regulate inflammation (RNA-Seq)
| PRJNA339997 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-06-10 | GSE86011 | GEO
Project description:STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation. Elucidating the contribution of somatic mutations to cancer is essential for personalized medicine. STK11 (LKB1) tumor suppressor appears to be inactivated in human cancer, however, somatic missense mutations also occur. Despite of our increased knowledge about LKB1 function, the role/s of these alterations in cancer are mostly unknown. Here, we investigated the contribution of four missense LKB1 somatic mutations in tumor biology. Three, out of the four mutants, lost their tumor suppressor capabilities and showed a deficient kinase activity. The remaining mutant conserved the enzymatic activity, but conferred an increased cell motility. Mechanistically, LKB1 mutants promoted the differential gene expression regulation of vesicle trafficking regulating molecules, adhesion molecules and cytokines, that correlated with the identified protein networks associated to the comparative secretome analysis. Notably, three mutant isoforms promoted tumor growth, and one of them induced inflammation and hemorrhagic tumors that correlated with the deregulated levels of cytokines. Altogether, our findings uncover oncogenic roles of LKB1 somatic mutations helping to understand their contribution to cancer.
2021-09-09 | PXD018041 | Pride
Project description:Diacylglycerol lipase-beta (DAGLβ) serves as a principal 2-arachidonoylglycerol (2-AG) biosynthetic enzyme regulating endocannabinoid and eicosanoid metabolism in immune cells including macrophages and dendritic cells. Genetic or pharmacological inactivation of DAGLβ ameliorates inflammation and hyper-nociception in preclinical models of pathogenic pain. These beneficial effects have been assigned principally to reductions in downstream proinflammatory lipid signaling, leaving alternative mechanisms of regulation largely underexplored. Here, we apply quantitative chemical- and phospho-proteomics to find that disruption of DAGLβ in primary macrophages leads to LKB1–AMPK signaling activation, resulting in reprogramming of the phosphoproteome and bioenergetics. Notably, AMPK inhibition reversed the antinociceptive effects of DAGLβ blockade, thereby directly supporting DAGLβ–AMPK crosstalk in vivo. Our findings uncover signaling between endocannabinoid biosynthetic enzymes and ancient energy-sensing kinases to mediate cell biological and pain responses.
2024-01-02 | PXD047413 | Pride
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2010-10-06 | E-MEXP-2444 | biostudies-arrayexpress
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