Immunophilin Functionality in Cellular Signaling

Immunophilins are a family of highly conserved proteins characterised by peptidyl-prolyl isomerase activity and, in many members, tetratricopeptide-repeat domains that mediate binding to the heat-shock protein Hsp90. Through these functional modules, immunophilins act both as enzymatic catalysts that accelerate the cis–trans isomerisation of proline residues and as scaffolds that organise multiprotein signalling complexes. They regulate a broad array of cellular pathways, including steroid receptor activation, NF-κB signalling, Akt kinase modulation and endoplasmic reticulum stress responses. By fine-tuning protein conformations, trafficking and post-translational modifications such as ubiquitination, immunophilins influence cell fate decisions, metabolic homeostasis and stress resilience. Their ubiquitous expression and involvement in fundamental signalling networks underpin their significance in physiology and pathology, with emerging roles in cancer, neurodegeneration, metabolic disease and immune regulation. The capacity of immunophilins to integrate chaperone-assisted folding with dynamic assembly of signalosomes makes them promising targets for therapeutic intervention.

Research from Nature Portfolio

Recent studies have revealed a direct link between stress-induced immunophilin expression and glucose homeostasis. Functional deletion or pharmacological antagonism of a prominent immunophilin enhances insulin-stimulated glucose uptake in muscle by promoting phosphorylation of the Akt substrate AS160 and increasing translocation of glucose transporter 4 to the plasma membrane. These interventions protect against diet-induced weight gain and improve glucose tolerance independently of body weight changes. Mechanistic investigation identified a novel association between the immunophilin and key elements of the insulin-responsive signalling cascade, positioning this protein as a mediator between chronic stress and metabolic dysfunction.

Immunophilin Functionality in Cellular Signaling publication trend

The graph below shows the total number of articles in immunophilin functionality in cellular signaling across all publications each year (not limited to Nature Index journals).

Technical terms

Immunophilin: A protein with peptidyl-prolyl isomerase activity that often contains tetratricopeptide repeats to bind chaperones and regulate client proteins.

Peptidyl-prolyl isomerase (PPIase): Enzyme that accelerates the cis–trans isomerisation of peptide bonds preceding proline residues, influencing protein folding and function.

Tetratricopeptide repeat (TPR): A structural motif of tandem helical repeats that mediates protein–protein interactions, notably with Hsp90.

Ubiquitination: Covalent attachment of ubiquitin to a target protein, directing its activity, localisation or degradation.

Cochaperone: A protein that associates with molecular chaperones like Hsp90 to facilitate client protein folding and complex assembly.

Endoplasmic reticulum (ER) stress: A cellular condition triggered by accumulation of misfolded proteins in the ER, activating adaptive signalling cascades.

ASK1–p38 signalling: A kinase cascade activated by stress stimuli that regulates apoptosis, inflammation and cell survival.

Akt kinase: A serine/threonine protein kinase central to cell growth, survival and metabolic regulation.

References

1. FKBP Family Proteins: Immunophilins with Versatile Biological Functions. Neurosignals (2008).
2. Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function. Nature Communications (2017).
3. FKBP51 plays an essential role in Akt ubiquitination that requires Hsp90 and PHLPP. Cell Death & Disease (2023).
4. The stability of FKBP9 maintained by BiP is crucial for glioma progression. Genes & Diseases (2023).
5. Structure-based discovery of small molecule inhibitors of FKBP51-Hsp90 protein-protein interaction. European Journal of Medicinal Chemistry (2024).