The role of heat shock protein 90 in idiopathic pulmonary fibrosis: state of the art

Abstract

Heat shock protein 90 (HSP 90) and its isoforms are a group of homodimeric proteins that regulate several cellular processes, such as the elimination of misfolded proteins, cell development and post-translational modifications of kinase proteins and receptors. Due to its involvement in extracellular matrix (ECM) remodelling, myofibroblast differentiation and apoptosis, HSP 90 has been investigated as a key player in the pathogenesis of lung fibrosis. Idiopathic pulmonary fibrosis (IPF) is the most common and deadly interstitial lung disease, due to the progressive distortion of lung parenchyma related to the overproduction and deposition of altered ECM, driven by transforming growth factor-β (TGF-β) dependent and independent pathways. The inhibition or induction of HSP 90 is associated with a reduced or increased expression of TGF-β receptors, respectively, suggesting a role for HSP 90 as a biomarker and therapeutic target in IPF. Experimental drugs such as geldanamycin and its derivatives 17-AAG (17-N-allylamino-17-demethoxygeldanamicin) and 17-DMAG (17-dimethylaminoethylamino-17-demethoxigeldanamycin), along with AUY-922, 1G6-D7, AT-13387, TAS-116 and myricetin, have been found to reduce lung fibrosis in both in vivo and in vitro models, supporting the role of this emerging target. This review aims to illustrate the structure and biological function of HSP 90 in the context of IPF pathobiology, as well as perspective application of this molecule as a biomarker and therapeutic target for IPF.

FIGURE 1

The structure, function and inhibitor targets of heat shock protein (HSP) 90. The chaperone consists of three domains: carboxy-terminal domain (CTD), amino-terminal domain (NTD) and a middle domain (MD). The CTD domain represents the site of dimerisation and interaction with co-chaperone sites. It also serves as additional pocket for the binding of adenosine triphosphate (ATP) and HSP 90 inhibitors (AUY-922). The NTD carries a binding site for both HSP 90 inhibitors including geldanamycin, 17-N-allylamino-17-demethoxygeldanamicin (17-AAG), 17-dimethylaminoethylamino-17-demethoxigeldanamycin (17-DMAG) and AT-13387 as well as ATP molecules, which are hydrolysed into adenosine diphosphate and inorganic phosphate. The MD embeds two-alpha helices with three irregular and six regular turns and exhibits a one-three-layer alpha–beta–alpha sandwich arrangement. As per the NTD, it is involved in the binding of co-chaperones and in ATPase activity. Furthermore, TAS-116, 1G6-D7 and myricetin are HSP 90 inhibitors that recognise different mechanisms of action. While TAS-116 exerts its inhibitory effect on HSP 90α and HSP 90β isoforms including extracellular signal-regulated kinase (ERK), 1G6-D7 and myricetin inhibits the chaperonin via extracellular HSP 90 dual lysin region binding and transforming growth factor-beta (TGF-β) and suppressor of mothers against decapentaplegic (SMAD) cytoplasmic proteins group downregulation.

FIGURE 2

The role of heat shock protein (HSP) 90 in fibrosis molecular cascade. Throughout inflammation, stress conditions or cell injury, HSP 90 concentration increases. This chaperonin is activated by a phosphorylation process mediated by mitogen-activated protein kinase (MAPK). HSP 90 activated form binds cell division cycle 37 (CDC37), enhances extracellular signal-regulated kinase (ERK), protein kinase B (AKT) and P38 and stabilises TGF-β receptors. The complexes HSP90–CDC37 and AKT–phophatidylinositol-3-kinase protein (PI3K) activate suppressor of mothers against decapentaplegic (SMAD) proteins and testis-specific serine-threonine kinase 4 (TSSK4) which, in turn, regulate gene expression after translocation into the nucleus. All in all, the regulation of nuclear transcription results in alveolar epithelial cell (AEC) apoptosis, epithelial–mesenchymal transition (EMT), fibroblast survival and proliferation, and increased expression of α-smooth muscle actin leading to lung fibrosis. Conversely, both ubiquitination and SMAD inhibition suppress HSP 90, by reducing transforming growth factor-β (TGF-β) receptor expression potentially acting as an antifibrotic.