Knr4: a disordered hub protein at the heart of fungal cell wall signalling

Martin-Yken, Hélène; François, Jean; Zerbib, Didier

doi:10.1111/cmi.12618

Cited by 17 publications

(44 citation statements)

References 87 publications

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“…Although, IDPs in general have not been much appreciated as therapeutic targets since their inability to adopt well-defined structures provides significant obstacles for developing ligands that regulate their behaviors, emerging evidence indicates that indeed, they can be specifically targeted (Wójcik et al, 2018;Neira et al, 2017;Martin-Yken et al, 2016;Yu et al, 2016;Berg, 2011;Jung et al, 2015;Ambadipudi and Zweckstetter, 2016). In fact, even transcription factors that were never the favourite drug targets, are now emerging as tractable to drug development (Tsafou et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis

Mohanty¹,

Nam²,

Pozhitkov³

et al. 2019

Preprint

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Tumor heterogeneity and cisplatin resistance are a major cause of tumor relapse and poor survival. Here we show that in lung adenocarcinoma (LUAD), paxillin (PXN) and integrin beta 4 (ITGB4) are associated with tumor progression, and cisplatin resistance. Silencing PXN and ITGB4 render cisplatin tolerant cells sensitive, and immunologically neutralizing ITGB4 improves sensitivity. The N-terminal half of PXN is intrinsically disordered and interacts with ITGB4 to regulate expression of USP1 and VDAC1 which are required for maintaining genomic stability and mitochondrial function in LUAD. By virtual screening an FDA-approved compound library, we identified compounds that interact with PXN in silico and attenuate cisplatin resistance in LUAD cells. RNAseq analysis identified a double negative feedback loop between ITGB4 and microRNA miR-1-3p, suggesting that bistability could lead to stochastic switching between cisplatinsensitive and resistant states in these cells. The data highlight an alternate, nongenetic, mechanism underlying chemoresistance in lung cancer.

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Section: Discussionmentioning

confidence: 99%

A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis

Mohanty¹,

Nam²,

Pozhitkov³

et al. 2019

Preprint

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“…More recently, it has been shown that Pkc1-Slt2 and calcineurin pathways cooperate to allow cell survival under compressive mechanical stress [290]. Knr4, an intrinsically disordered protein, has been proposed to serve as connecting node between these two signal transmission pathways [291].…”

Section: Pp2b (Pp3 Calcineurin) and Pp2b-related Enzymesmentioning

confidence: 99%

Ser/Thr protein phosphatases in fungi: structure, regulation and function

2019

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Reversible phospho-dephosphorylation of proteins is a major mechanism for the control of cellular functions. By large, Ser and Thr are the most frequently residues phosphorylated in eukar-yotes. Removal of phosphate from these amino acids is catalyzed by a large family of well-conserved enzymes, collectively called Ser/Thr protein phosphatases. The activity of these enzymes has an enormous impact on cellular functioning. In this work we pre-sent the members of this family in S. cerevisiae and other fungal species, and review the most recent findings concerning their regu-lation and the roles they play in the most diverse aspects of cell biology.

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“…S2 ). The C-terminus of Knr4 is largely unstructured and not directly necessary for protein function in S. cerevisiae ( Dagkessamanskaia et al, 2010 , Martin-Yken et al, 2016 ). Hence, we tested the ability of the C. albicans SMI1 gene, retaining its two ambiguous codons, to complement the cell wall-related phenotypes of S. cerevisiae knr4 null mutants.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, the role of Smi1 in the control of cell wall synthesis, cellular adhesion and drug resistance is relevant to the search for new antifungal targets. An advantage of Smi1 as a drug target over Hsp90, calcineurin, Pkc1 or other MAP kinases is the specificity of the Knr4/Smi1 superfamily of proteins to the Fungal Kingdom as it is absent from host cells ( Martin-Yken et al, 2016 ). In addition, since this protein family is conserved among fungi, including other fungal pathogens of mammals ( C. glabrata and Aspergillus species notably) and also plants (ex: Magnaporthe grisea ), developing drugs that target Smi1 might lead to broader antifungal applications in domains such as agriculture.…”

Section: Discussionmentioning

confidence: 99%

“…Here we describe the role of Smi1, a C. albicans protein homologous to the Saccharomyces cerevisiae hub protein, Knr4, which interacts physically with both the Slt2 MAP kinase and calcineurin, thus connecting the two primary signaling pathways involved in cell wall maintenance during stress: the cell wall integrity pathway (CWI) and the calcineurin pathway ( Dagkessamanskaia et al, 2010 , Martin-Yken et al, 2016 ). Although its precise molecular mode of action is currently unknown, it has been shown that two conserved serine residues, S 200 and S 203, phosphorylated in vivo , are essential for Krn4 function in signal transmission ( Ficarro et al, 2002 , Basmaji et al, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

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A conserved fungal hub protein involved in adhesion and drug resistance in the human pathogen Candida albicans

et al. 2018

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Drug resistance and cellular adhesion are two key elements of both dissemination and prevalence of the human fungal pathogen Candida albicans . Smi1 belongs to a family of hub proteins conserved among the fungal kingdom whose functions in cellular signaling affect morphogenesis, cell wall synthesis and stress resistance. The data presented here indicate that C. albicans SMI1 is a functional homolog of Saccharomyces cerevisiae KNR4 and is involved in the regulation of cell wall synthesis. Expression of SMI1 in S. cerevisiae knr4 Δ null mutants rescued their sensitivity to caspofungin and to heat stress. Deletion of SMI1 in C. albicans resulted in sensitivity to the cell-wall-perturbing compounds Calcofluor White and Caspofungin. Analysis of wild-type and mutant cells by Atomic Force Microscopy showed that the Young’s Modulus (stiffness) of the cell wall was reduced by 85% upon deletion of SMI1 , while cell surface adhesion measured by Force Spectroscopy showed that the surface expression of adhesive molecules was also reduced in the mutant. Over-expression of SMI1 , on the contrary, increased cell surface adhesion by 6-fold vs the control strain. Finally, Smi1-GFP localized as cytoplasmic patches and concentrated spots at the sites of new cell wall synthesis including the tips of growing hyphae, consistent with a role in cell wall regulation. Thus, Smi1 function appears to be conserved across fungi, including the yeast S. cerevisiae, the yeast and hyphal forms of C. albicans and the filamentous fungus Neurospora crassa .

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Knr4: a disordered hub protein at the heart of fungal cell wall signalling

Cited by 17 publications

References 87 publications

A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis

A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis

Ser/Thr protein phosphatases in fungi: structure, regulation and function

A conserved fungal hub protein involved in adhesion and drug resistance in the human pathogen Candida albicans

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