Role of Heat Shock Protein 90 in Regulating Downstream Signal Transduction Cascades

W, Lei; Duron, David I.; Stine, Carrie; Streicher, John M.

doi:10.1007/978-3-030-03952-3_9

Cited by 1 publication

(1 citation statement)

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“…There are four isoforms in the Hsp90 family: Hsp90α, Hsp90β, GRP94, and TRAP1. Hsp90α and Hsp90β are the major isoforms, expressed predominantly within the cytoplasm, while GRP94 is expressed in the endoplasmic reticulum and TRAP1 in the mitochondria ( Hoter et al, 2018 ; Lei et al, 2019 ). Each isoform of Hsp90 has different client proteins, although they share a high rate of similarity on structure ( Hoter et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory activities of novel heat shock protein 90 isoform selective inhibitors in BV-2 microglial cells

Smith,

Kliebe,

Mishra

et al. 2024

Front. Mol. Biosci.

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Heat shock protein 90 (Hsp90) is a family of chaperone proteins that consists of four isoforms: Hsp90α, Hsp90β, glucose-regulated protein 94 (Grp94), and tumor necrosis factor type 1 receptor-associated protein (TRAP1). They are involved in modulating the folding, maturation, and activation of their client proteins to regulate numerous intracellular signaling pathways. Previous studies demonstrated that pan-Hsp90 inhibitors reduce inflammatory signaling pathways resulting in a reduction of inflammation and pain but show toxicities in cancer-related clinical trials. Further, the role of Hsp90 isoforms in inflammation remains poorly understood. This study aimed to determine anti-inflammatory activities of Hsp90 isoforms selective inhibitors on the lipopolysaccharide (LPS)-induced inflammation in BV-2 cells, a murine microglial cell line. The production of inflammatory mediators such as nitric oxide (NO), interleukin 1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) was measured. We also investigated the impact of Hsp90 isoform inhibitors on the activation of nuclear factor kappa B (NF-κB), nuclear factor erythroid 2–related factor 2 (Nrf2), and mitogen-activated protein kinases (MAPKs). We found that selective inhibitors of Hsp90β reduced the LPS-induced production of NO, IL-1β, and TNF-α via diminishing the activation of NF-κB and Extracellular signal-regulated kinases (ERK) MAPK. The Hsp90α, Grp94, TRAP1 inhibitors had limited effect on the production of inflammatory mediators. These findings suggest that Hsp90β is the key player in LPS-induced neuroinflammation. Thereby providing a more selective drug target for development of medications involved in pain management that can potentially contribute to the reduction of adverse side effects associated with Hsp90 pan inhibitors.

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Section: Introductionmentioning

confidence: 99%