Cyclophilins and their possible role in the stress response

Abstract

Cyclophilins are proteins which are remarkably conserved through evolution; moreover they have been found in every possible existing organism, which indicates their fundamental importance. Due to their enzymatic properties, multiplicity, cellular localization and role in protein folding they belong to the group of proteins termed molecular chaperones. All the proteins of the cyclophilin family possess enzymatic peptidyl-prolyl isomerase activity (PPI-ase), which is essential to protein folding in vivo. Recently PPI-ase activity was suggested as playing a role in regulation of transcription and differentiation. However, not all cyclophilin functions are explained by PPI-ase activity. For instance, one of the cyclophilins plays a regulatory role in the heat shock response and the mitochondrial cyclophilin (Cyclophilin D) is an integral part of the mitochondrial permeability transition complex, which is regarded as having a crucial role in mechanisms of cell death. In support of a role in the stress response, the expression of certain cyclophilins has recently been shown to be up-regulated under various stressful conditions. Current evidence of functional involvement of cyclophilins in various intracellular pathways is reviewed along with the indications that cyclophilin D (Cyp D) represents a crucial part of the mitochondrial permeability transition pore, which is detrimental in apoptotic and necrotic cell death. This review does not attempt to cover all the existing information related to cyclophilin family of proteins, but focus on the existing evidence of the involvement of these proteins in the intracellular stress response.

Figure 1

Schematic representation of the mitochondrial chaperone complex. Cytosolic heat shock protein (c-hsp70); mitochondrial heat shock protein 70 (m-hsp70), mitochondrial heat shock protein 60 (m-hsp 60), mitochondrial chaperone 10 (− cpn 10).

Figure 2

Representation of the CsA sensitive mitochondrial permeability transition pore (MPTP). CsA binds to the cyclophilin in the mitochondrial membrane in an ADP dependent manner. The exact composition of the MPTP is not fully known, but it is thought to involve proteins from the cytosol including voltage dependent anion channel (VDAC), the adenine nucleotide translocator (ANT), mitochondrial cyclophilin D, the antiapoptotic proteins BCL-2, proapoptotic protein Bax, and hexokinase. Evidence exists for the involvement of these proapoptotic and antiapoptotic proteins in the formation of the MPTP complex in addition to the previously described proteins such as ANT, VDAC, cyclophilin D and hexokinase.

Figure 3

The immunosuppressive effects of CsA and FK 506 originate from the binding of the drug-immunophilin complex to molecules of calcineurin (CN) and subsequent interaction with calmodulin (CAM). De-phosphorylation of activated T-cells class of transcription factors (NFAT) inhibits their translocation to the cell nucleus and subsequent activation of interleukin-2 (IL-2) expression. Activation of calcineurin leads to induction of nitric oxide synthase (NOS) by a dephosphorylation mechanism, overproduction of nitric oxide (NO) and cell death.

Figure 4

Representation of the IP₃ receptor which regulates calcium release from endoplasmic reticulum. FKBP anchors calcineurin to the IP₃ receptor complexes and calcium flux is regulated by a mechanism involving calcineurin phosphatase activity which is disrupted by FK 506.