Identification of a Lysosomal Pathway That Modulates Glucocorticoid Signaling and the Inflammatory Response

Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503, USA.
Science Signaling (Impact Factor: 6.28). 07/2011; 4(180):ra44. DOI: 10.1126/scisignal.2001450
Source: PubMed


The antimalaria drug chloroquine has been used as an anti-inflammatory agent for treating systemic lupus erythematosus and rheumatoid arthritis. We report that chloroquine promoted the transrepression of proinflammatory cytokines by the glucocorticoid receptor (GR). In a mouse collagen-induced arthritis model, chloroquine enhanced the therapeutic effects of glucocorticoid treatment. By inhibiting lysosome function, chloroquine synergistically activated glucocorticoid signaling. Lysosomal inhibition by either bafilomycin A1 (an inhibitor of the vacuolar adenosine triphosphatase) or knockdown of transcription factor EB (TFEB, a master activator of lysosomal biogenesis) mimicked the effects of chloroquine. The abundance of the GR, as well as that of the androgen receptor and estrogen receptor, correlated with changes in lysosomal biogenesis. Thus, we showed that glucocorticoid signaling is regulated by lysosomes, which provides a mechanistic basis for treating inflammation and autoimmune diseases with a combination of glucocorticoids and lysosomal inhibitors.

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Available from: Jeffrey P MacKeigan, Sep 19, 2014
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    • "Indeed, biochemical experiments performed in rat uterine cells showed that radioactive E2 has been found in sub-cellular fractions corresponding to the lysosome-enriched compartment [14], gold-labelled E2 conjugated with BSA (i.e., gold E2-BSA) was observed in lysososmes of HepG2 cells by electron microscopy [15] and fluorescent labelled E2-BSA or transfected GFP-tagged ERα were separately shown to co-localize with lysotracker in NR-38 neurons [16]. Moreover, the glucocorticoid receptor degradation was found to be partially dependent on lysosomes in modified human embryonic kidney AD293 cells [29]. Thus, lysosome-based degradation contributes to the regulation of the cellular content of both ERα and other nuclear receptors. "
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