Calcineurin regulation of cytoskeleton organization: a new paradigm to analyse the effects of calcineurin inhibitors on the kidney

Abstract

Calcineurin is a serine/threonine phosphatase originally involved in the immune response but is also known for its role as a central mediator in various non-immunological intracellular signals. The nuclear factor of activated T cell (NFAT) proteins are the most widely described substrates of calcineurin, but ongoing work has uncovered other substrates among which are the cytoskeleton organizing proteins (i.e. cofilin, synaptopodin, WAVE-1). Control over cytoskeletal proteins is of outmost interest because the phenotypic properties of cells are dependent on cytoskeleton architecture integrity, while rearrangements of the cytoskeleton are implicated in both physiological and pathological processes. Previous works investigating the role of calcineurin on the cytoskeleton have focused on neurite elongation, myocyte hypertrophic response and recently in kidney cells structure. Nuclear factor of activated T cell activation is expectedly identified in the signalling pathways for calcineurin-induced cytoskeleton organization, however new NFAT-independent pathways have also been uncovered. The aim of this review is to summarize the current knowledge on the effects of calcineurin on cytoskeletal proteins and related intracellular pathways. These newly described properties of calcineurin on cytoskeletal proteins may explain some of the beneficial or deleterious effects observed in kidney cells associated with the use of the calcineurin inhibitors, cyclosporine and tacrolimus.

Investigating the human Calcineurin Interaction Network using the πɸLxVP SLiM

“…2B), consistent with the known roles of CN to dephosphorylate transcription factors and DNA binding proteins that are critical for the G1-S transition of the cell cycle2122. The large distribution of πɸLxVP-proteins in the membrane (18%) and intracellular transport (13%) is also consistent with the prominent roles of CN in ion transport and vesicle trafficking, respectively2324.…”

Endoplasmic Reticulum Stress Predicts Clinical Response to Cyclosporine Treatment in Primary Membranous Nephropathy

“…CNIs have also been suggested to be cytoprotective in podocytes through the inhibition of synaptopodin degradation and stabilization of the podocyte actin cytoskeleton [28]. Cyclosporine has also been shown to induce stiffening of the actin network in tubular structure, which may alter the response of proximal cells to modifications of tubular flow, potentially exerting a detrimental effect on tubular structure [29]. The physiologic role of calcineurin in kidney cells had largely remained unknown until the exhibition of abnormal kidney development in mice with knockouts for the calcineurin Aα subunit [30].…”

Cyclosporine A inhibits MRTF‐SRF signaling through Na + /K + ATPase inhibition and actin remodeling

“…In PTC, we demonstrated that the actin cytoskeleton could be modified by CsA. 42 Indeed, independently from the inhibition of NFAT, CsA triggered a reversible disorganization of actin scaffolding at the periphery of the cell. Whether a mechanism involving the CsA-related regulation of CFL was responsible for the effects of CsA on PTC remained to be addressed.…”

“…In the light of early observations of CsA effects on the actin cytoskeleton of podocytes, the study of the actin dynamic in PTC appeared of utmost interest in the elucidation of pathophysiological mechanisms of TA upon CNI exposure. In PTC, we demonstrated that the actin cytoskeleton could be modified by CsA . Indeed, independently from the inhibition of NFAT, CsA triggered a reversible disorganization of actin scaffolding at the periphery of the cell.…”