c-Maf inducing protein inhibits cofilin-1 activity and alters podocyte cytoskeleton organization

Liu, Yu; Ye, Jianming; Liu, Qifeng; Feng, Jianhua; Gu, Xiaoxia; Sun, Qiang; Lu, Guoyuan

doi:10.3892/mmr.2017.7156

Cited by 8 publications

(4 citation statements)

References 28 publications

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“…These results, along with other data obtained from the transgenic mouse model, suggest a defect in T cell activation associated with CMIP expression. Based on these findings, we further analyzed the expression of Cofilin-1, a major actor in the dynamic rearrangement of the actin cytoskeleton 23 whose activity was recently reported to be negatively regulated by CMIP in podocytes, 24 by Western blotting. We found that phosphorylated Cofilin-1, the inactive form of Cofilin-1, was dramatically increased in transgenic T cells at 60 min after stimulation compared to its levels in WT T cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

CMIP is a negative regulator of T cell signaling

Oniszczuk

Sendeyo

Chhuon³

et al. 2019

Cell Mol Immunol

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Upon their interaction with cognate antigen, T cells integrate different extracellular and intracellular signals involving basal and induced protein–protein interactions, as well as the binding of proteins to lipids, which can lead to either cell activation or inhibition. Here, we show that the selective T cell expression of CMIP, a new adapter protein, by targeted transgenesis drives T cells toward a naïve phenotype. We found that CMIP inhibits activation of the Src kinases Fyn and Lck after CD3/CD28 costimulation and the subsequent localization of Fyn and Lck to LRs. Video microscopy analysis showed that CMIP blocks the recruitment of LAT and the lipid raft marker cholera toxin B at the site of TCR engagement. Proteomic analysis identified several protein clusters differentially modulated by CMIP and, notably, Cofilin-1, which is inactivated in CMIP-expressing T cells. Moreover, transgenic T cells exhibited the downregulation of GM3 synthase, a key enzyme involved in the biosynthesis of gangliosides. These results suggest that CMIP negatively impacts proximal signaling and cytoskeletal rearrangement and defines a new mechanism for the negative regulation of T cells that could be a therapeutic target.

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Section: Resultsmentioning

confidence: 99%

CMIP is a negative regulator of T cell signaling

Oniszczuk

Sendeyo

Chhuon³

et al. 2019

Cell Mol Immunol

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“…Interestingly, silencing c-mip prevented IL-17 related podocyte apoptosis by promoting persistent activation of NF-κB and upregulation of anti-apoptotic protein Bcl-2 (137). C-mip is a protein whose expression is suppressed in healthy glomeruli (138) and increased in pathological conditions and has been associated with cytoskeletal disorganization in podocytes and proteinuria (139,140).…”

Section: Podocytesmentioning

confidence: 99%

The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

Paquissi

Abensur

2021

Front. Med.

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Systemic lupus erythematosus (SLE) is a disease characterized by dysregulation and hyperreactivity of the immune response at various levels, including hyperactivation of effector cell subtypes, autoantibodies production, immune complex formation, and deposition in tissues. The consequences of hyperreactivity to the self are systemic and local inflammation and tissue damage in multiple organs. Lupus nephritis (LN) is one of the most worrying manifestations of SLE, and most patients have this involvement at some point in the course of the disease. Among the effector cells involved, the Th17, a subtype of T helper cells (CD4+), has shown significant hyperactivation and participates in kidney damage and many other organs. Th17 cells have IL-17A and IL-17F as main cytokines with receptors expressed in most renal cells, being involved in the activation of many proinflammatory and profibrotic pathways. The Th17/IL-17 axis promotes and maintains repetitive tissue damage and maladaptive repair; leading to fibrosis, loss of organ architecture and function. In the podocytes, the Th17/IL-17 axis effects include changes of the cytoskeleton with increased motility, decreased expression of health proteins, increased oxidative stress, and activation of the inflammasome and caspases resulting in podocytes apoptosis. In renal tubular epithelial cells, the Th17/IL-17 axis promotes the activation of profibrotic pathways such as increased TGF-β expression and epithelial-mesenchymal transition (EMT) with consequent increase of extracellular matrix proteins. In addition, the IL-17 promotes a proinflammatory environment by stimulating the synthesis of inflammatory cytokines by intrinsic renal cells and immune cells, and the synthesis of growth factors and chemokines, which together result in granulopoiesis/myelopoiesis, and further recruitment of immune cells to the kidney. The purpose of this work is to present the prognostic and immunopathologic role of the Th17/IL-17 axis in Kidney diseases, with a special focus on LN, including its exploration as a potential immunotherapeutic target in this complication.

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“…Cofilin is essential for maintaining normal podocyte structure and facilitating structural changes in actin during podocyte injury and recovery. Cofilin knockout mice develop persistent proteinuria by 3 months of age and exhibit more severe proteinuria along with foot protrusions by 18 months of age [ 66 ]. The RhoA/ROCK/LIMK1 pathway can mediate cofilin phosphorylation, altering the ratio of phosphorylated to nonphosphorylated cofilin and disrupting actin dynamics, ultimately leading to cytoskeletal damage [ 67 , 68 ].…”

Section: Discussionmentioning

confidence: 99%

Klotho Stabilizes the Podocyte Actin Cytoskeleton in Idiopathic Membranous Nephropathy through Regulating the TRPC6/CatL Pathway

Wang,

Liu,

Cheng

et al. 2024

Am J Nephrol

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Introduction: The aim of this study was to explore the renoprotective effects of Klotho on podocyte injury mediated by complement activation and autoantibodies in idiopathic membranous nephropathy (IMN). Methods: Rat passive Heymann nephritis (PHN) was induced as an IMN model. Urine protein levels, serum biochemistry, kidney histology, and podocyte marker levels were assessed. In vitro, sublytic podocyte injury was induced by C5b-9. The expression of Klotho, transient receptor potential channel 6 (TRPC6), and cathepsin L (CatL); its substrate synaptopodin; and the intracellular Ca2+ concentration were detected via immunofluorescence. RhoA/ROCK pathway activity was measured by an activity quantitative detection kit, and the protein expression of phosphorylated-LIMK1 (p-LIMK1) and p-cofilin in podocytes was detected via Western blotting. Klotho knockdown and overexpression were performed to evaluate its role in regulating the TRPC6/CatL pathway. Results: PHN rats exhibited proteinuria, podocyte foot process effacement, decreased Klotho and Synaptopodin levels, and increased TRPC6 and CatL expression. The RhoA/ROCK pathway was activated by the increased phosphorylation of LIMK1 and cofilin. Similar changes were observed in C5b-9-injured podocytes. Klotho knockdown exacerbated podocyte injury, while Klotho overexpression partially ameliorated podocyte injury. Conclusion: Klotho may protect against podocyte injury in IMN patients by inhibiting the TRPC6/CatL pathway. Klotho is a potential target for reducing proteinuria in IMN patients.

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c-Maf inducing protein inhibits cofilin-1 activity and alters podocyte cytoskeleton organization

Cited by 8 publications

References 28 publications

CMIP is a negative regulator of T cell signaling

CMIP is a negative regulator of T cell signaling

The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

Klotho Stabilizes the Podocyte Actin Cytoskeleton in Idiopathic Membranous Nephropathy through Regulating the TRPC6/CatL Pathway

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