Prohibitins function as endogenous ligands for Siglec-9 and negatively regulate TCR signaling upon ligation

Yurugi, Hajime; Tanida, Shuhei; Akita, Kaoru; Ishida, Akiko; Toda, Munetoyo

doi:10.1016/j.bbrc.2013.03.085

Cited by 11 publications

(10 citation statements)

References 21 publications

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“…Because Prohibitins are exposed to the external membrane of activated T cells 37 we asked whether Prohibitins were also present at the external surface of Schwann cells. We biotinylated Schwann cells, and followed by either streptavidin pull-down and blotting with anti-Prohibitin-2 antibodies ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In T-cells, Prohibitins translocate to the plasma membrane on activation 54 and binds to Siglec-9 on other immune cells 37 . We showed that Prohibitin-2 interacts with Schwann cells membrane proteins, and increased in pseudopods after induction with neuronal membranes, suggesting that axons may induce a redistribution of Prohibitin to pseudopods to promote Schwann cell–axon interactions.…”

Section: Discussionmentioning

confidence: 99%

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Spatial mapping of juxtacrine axo-glial interactions identifies novel molecules in peripheral myelination

et al. 2015

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Cell–cell interactions promote juxtacrine signals in specific subcellular domains, which are difficult to capture in the complexity of the nervous system. For example, contact between axons and Schwann cells triggers signals required for radial sorting and myelination. Failure in this interaction causes dysmyelination and axonal degeneration. Despite its importance, few molecules at the axo-glial surface are known. To identify novel molecules in axo-glial interactions, we modified the ‘pseudopodia' sub-fractionation system and isolated the projections that glia extend when they receive juxtacrine signals from axons. By proteomics we identified the signalling networks present at the glial-leading edge, and novel proteins, including members of the Prohibitin family. Glial-specific deletion of Prohibitin-2 in mice impairs axo-glial interactions and myelination. We thus validate a novel method to model morphogenesis and juxtacrine signalling, provide insights into the molecular organization of the axo-glial contact, and identify a novel class of molecules in myelination.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Spatial mapping of juxtacrine axo-glial interactions identifies novel molecules in peripheral myelination

et al. 2015

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“…There are a number of reports that have identified PHB1 as a membrane-associated protein in T cells and have demonstrated its role in T-cell receptor signaling. 12 , 23 , 47 Stimulation of murine T cells with anti-CD3 and anti-CD28 antibodies remarkably induces the cell surface expression of PHB1, 12 which presumably participates in the T-cell receptor-mediated signaling cascade. PHB1 has been shown to be an endogenous ligand for sialic acid-binding lectin-9 (siglec-9) and negatively regulates T-cell signaling.…”

Section: Tyrosine Phosphorylation Of Phb1 In T Cell Signalingmentioning

confidence: 99%

“…PHB1 has been shown to be an endogenous ligand for sialic acid-binding lectin-9 (siglec-9) and negatively regulates T-cell signaling. 47 Furthermore, Salmonella typhi, which causes systemic infection and typhoid in humans, targets PHB1 on T cells and downregulates T-cell-mediated immune signaling. 48 , 49 In a separate study, to identify differentially expressed proteins upon activation of human T cells, Ross et al 23 found that the expression levels of PHB1 and PHB2 mRNA and protein were highly upregulated upon T-cell activation.…”

Section: Tyrosine Phosphorylation Of Phb1 In T Cell Signalingmentioning

confidence: 99%

Prohibitin: a potential therapeutic target in tyrosine kinase signaling

Ande

Mishra

2017

Sig Transduct Target Ther

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Prohibitin is a pleiotropic protein that has roles in fundamental cellular processes, such as cellular proliferation and mitochondrial housekeeping, and in cell- or tissue-specific functions, such as adipogenesis and immune cell functions. The different functions of prohibitin are mediated by its cell compartment-specific attributes, which include acting as an adaptor molecule in membrane signaling, a scaffolding protein in mitochondria, and a transcriptional co-regulator in the nucleus. However, the precise relationship between its distinct cellular localization and diverse functions remain largely unknown. Accumulating evidence suggests that the phosphorylation of prohibitin plays a role in a number of cell signaling pathways and in intracellular trafficking. Herein, we discuss the known and potential importance of the site-specific phosphorylation of prohibitin in regulating these features. We will discuss this in the context of new evidence from tissue-specific transgenic mouse models of prohibitin, including a mutant prohibitin lacking a crucial tyrosine phosphorylation site. We conclude with the opinion that prohibitin can be used as a potential target for tyrosine kinase signal transduction-targeting therapy, including in insulin, growth factors, and immune signaling pathways.

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“…In T cells, where PHBs are found to be surface-expressed upon activation, Siglec-9 expressed on antigen-presenting cells (APC) was identified to be a natural, physiological ligand of surface-exposed PHB1 (Yurugi et al, 2013). Siglec-9 binding to PHBs led to inhibition of MAPK signalling and IL-2 production.…”

Section: Introductionmentioning

confidence: 99%

Targeting prohibitins at the cell surface prevents Th17‐mediated autoimmunity

et al. 2018

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T helper (Th)17 cells represent a unique subset of CD4 T cells and are vital for clearance of extracellular pathogens including bacteria and fungi. However, Th17 cells are also involved in orchestrating autoimmunity. By employing quantitative surface proteomics, we found that the evolutionarily conserved prohibitins (PHB1/2) are highly expressed on the surface of both murine and human Th17 cells. Increased expression of PHBs at the cell surface contributed to enhanced CRAF/MAPK activation in Th17 cells. Targeting surface-expressed PHBs on Th17 cells with ligands such as Vi polysaccharide (Typhim vaccine) inhibited CRAF-MAPK pathway, reduced interleukin (IL)-17 expression and ameliorated disease pathology with an increase in FOXP3-expressing Tregs in an animal model for multiple sclerosis (MS). Interestingly, we detected a CD4 T cell population with high PHB1 surface expression in blood samples from MS patients in comparison with age- and sex-matched healthy subjects. Our observations suggest a pivotal role for the PHB-CRAF-MAPK signalling axis in regulating the polarization and pathogenicity of Th17 cells and unveil druggable targets in autoimmune disorders such as MS.

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Prohibitins function as endogenous ligands for Siglec-9 and negatively regulate TCR signaling upon ligation

Cited by 11 publications

References 21 publications

Spatial mapping of juxtacrine axo-glial interactions identifies novel molecules in peripheral myelination

Spatial mapping of juxtacrine axo-glial interactions identifies novel molecules in peripheral myelination

Prohibitin: a potential therapeutic target in tyrosine kinase signaling

Targeting prohibitins at the cell surface prevents Th17‐mediated autoimmunity

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