Diptoindonesin G, a new Hsp90 drug

Wickramaratne, Anushka; Wickner, Sue

doi:10.1016/j.jbc.2022.102826

Cited by 3 publications

(2 citation statements)

References 7 publications

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“…HSP90α is an important and abundant ATP-dependent molecular chaperone whose expression is induced by heat shock and other cellular stresses [10]. HSP90α plays an important role in cellular protein stabilization in eukaryotes by remodeling and activating client proteins such as signaling proteins, transcription factors, and regulatory kinases [30]. Tamspiramycin (17-AAG) is an effective HSP90α inhibitor that inhibits the chaperone action of HSP90α, causes the loss of function of HSP90α client proteins, and inhibits downstream signal transduction regulated by HSP90α [31].…”

Section: Discussionmentioning

confidence: 99%

Heat shock protein 90α reduces CD8+ T cell exhaustion in acute lung injury induced by lipopolysaccharide

Yan,

Chen,

Yang

et al. 2024

Cell Death Discov.

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CD8+ T-cell exhaustion is a promising prognostic indicator of sepsis-induced acute respiratory distress syndrome (ARDS). Patients with sepsis-related ARDS had reduced levels of HSP90AA1. However, whether the changes in CD8+ T cells were related to HSP90α, encoded by the HSP90AA1 gene, was unclear. This study aimed to examine the regulatory mechanism of HSP90α and its impact on CD8+ T-cell exhaustion in lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, by conducting a mouse model of ALI, we found that one week after LPS-induced ALI, CD8+ T cells showed exhaustion characteristics. At this time, proliferation and cytokine release in CD8+ T cells were reduced. The inhibitory costimulatory factors PD-1 and Tim-3, on the other hand, were enhanced. Meanwhile, the expression of HSP90α and STAT1 decreased significantly. The in vitro studies showed that HSP90α stimulation or inhibition affected the CD8+ T-cell exhaustion phenotype. Interference with STAT1 reduced the expression of HSP90α and impaired its regulation of CD8+ T cells. The Co-Immunoprecipitation results indicated that HSP90α can directly or indirectly bind to TOX to regulate TOX expression and downstream signal transduction. In summary, by inhibiting TOX-mediated exhaustion signaling pathways, HSP90α inhibited CD8+ T-cell exhaustion in ALI. The participation of STAT1 in the regulation of HSP90α was required.

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Section: Discussionmentioning

confidence: 99%

Heat shock protein 90α reduces CD8+ T cell exhaustion in acute lung injury induced by lipopolysaccharide

Yan,

Chen,

Yang

et al. 2024

Cell Death Discov.

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“…Among these, several key regulators of molecular signaling pathways that play important roles in mediating inflammation and other immune responses are client proteins of HSP90. These include various kinases (RIP/ERK/p38/MAPK), transcription factors (NF-kB, STAT, p53), NLRP3, Toll Like-Receptor-4 and others (Schopf et al, 2017;Biebl and Buchner, 2019;Wickramaratne and Wickner, 2023). HSP90 regulates NLRP3-mediated assembly of inflammasome which facilitates caspase-1-mediated maturation of IL-1β and promotes production of other inflammatory mediators as well (Piippo et al, 2018;Ranta-Aho et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

HSP90, a Common Therapeutic Target for Suppressing Skin Injury Caused by Exposure to Chemically Diverse Classes of Blistering Agents

Srivastava,

Muzaffar,

Khan

et al. 2023

J Pharmacol Exp Ther

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Vesicants such as arsenicals and mustards produce highly painful cutaneous inflammatory and blistering responses, hence, developed as chemical weapons during World War I/II. Here, using lewisite and sulfur mustard surrogates namely phenylarsine oxide (PAO) and 2-chloroethyl ethyl sulfide (CEES) respectively, we defined a common underlying mechanism of toxic action by these two distinct classes of vesicants. Murine skin exposure to these chemicals causes tissue destruction characterized by increase in skin bifold thickness, Draize score, infiltration of inflammatory cells and appearance of apoptotic epidermal and dermal cells. RNAseq analysis identified ~346 inflammatory genes that were commonly altered by both PAO and CEES along with identification of cytokine signaling activation as the top canonical pathway. Activation of several of these inflammatory genes and pathways are associated with phosphorylationdependent activation of heat shock protein 90α (p-HSP90α). Topical treatment with known HSP90 inhibitors, SNX-5422 and IPI-504 post PAO or CEES skin challenge significantly attenuated these chemical-induced skin damage (reduction in overall skin injury and clinical scores). In addition, highly upregulated inflammatory genes Saa3,

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