Extracellular Heat Shock Protein-90 (eHsp90): Everything You Need to Know

Abstract

“Extracellular” Heat Shock Protein-90 (Hsp90) was initially reported in the 1970s but was not formally recognized until 2008 at the 4th International Conference on The Hsp90 Chaperone Machine (Monastery Seeon, Germany). Studies presented under the topic of “extracellular Hsp90 (eHsp90)” at the conference provided direct evidence for eHsp90’s involvement in cancer invasion and skin wound healing. Over the past 15 years, studies have focused on the secretion, action, biological function, therapeutic targeting, preclinical evaluations, and clinical utility of eHsp90 using wound healing, tissue fibrosis, and tumour models both in vitro and in vivo. eHsp90 has emerged as a critical stress-responding molecule targeting each of the pathophysiological conditions. Despite the studies, our current understanding of several fundamental questions remains little beyond speculation. Does eHsp90 indeed originate from purposeful live cell secretion or rather from accidental dead cell leakage? Why did evolution create an intracellular chaperone that also functions as a secreted factor with reported extracellular duties that might be (easily) fulfilled by conventional secreted molecules? Is eHsp90 a safer and more optimal drug target than intracellular Hsp90 chaperone? In this review, we summarize how much we have learned about eHsp90, provide our conceptual views of the findings, and make recommendations on the future studies of eHsp90 for clinical relevance.

HSP90α induces immunosuppressive myeloid cells in melanoma via TLR4 signaling

“…It was shown that HSP90α was elevated in plasma of patients with various cancers and some non-cancer diseases such as psoriasis, chronic glomerulonephritis and idiopathic pulmonary fibrosis. 50 We found that an increased PD-L1 expression on circulating M-MDSC tended to correlate with higher HSP90α concentrations in plasma. Furthermore, patients with higher plasma levels of HSP90α showed a tendency for worse clinical outcome that goes in line with another publication.…”

Structural dynamics and immunogenicity of the recombinant and outer membrane vesicle-embedded Meningococcal antigen NadA

“…So far, the role and the mechanism adopted by Hsp90 in binding NadA has not been fully clarified. While the chaperone function of Hsp90 in remodeling unfolded proteins or binding to intrinsically disordered regions in the cellular cytosol is fully elucidated [45][46][47] , the establishment of its presence in the extracellular space is more recent and functionally less defined. Extracellular Hsp90 has been found to be involved in the entry of some viruses 48 as well as to modulate rNadA internalization and trafficking in epithelial cells and monocytes/macrophages stimulation [36][37][38] .…”

Structural and Dynamic Disturbances Revealed by Molecular Dynamics Simulations Predict the Impact on Function of CCT5 Chaperonin Mutations Associated with Rare Severe Distal Neuropathies

“…Its partners include the ubiquitin-proteasome system (UPS) and the chaperone-mediated autophagy machinery. The CS also has non-canonical functions relating to inflammatory and autoimmune conditions and cancer and interacts with the immune system (IS) [2][3][4][5][6][7][8][9]. The chief components of the CS are the molecular chaperones, encompassing a large variety of molecules that can be classified according to their molecular weight.…”