Editors' ChoiceEndometriosis

Cytosolic functions of ERβ in apoptosis and inflammasome regulation

Sci. Signal.  17 Nov 2015:
Vol. 8, Issue 403, pp. ec338
DOI: 10.1126/scisignal.aad8685

Endometriosis is an often painful condition, resulting from the ectopic growth of endometrial stromal and epithelial cells outside of the uterus. Endometriosis depends on estrogen, and endometriotic tissue has increased amounts of estrogen. By analyzing surgically induced endometriosis, Han et al. identified nontranscriptional effects of estrogen that were mediated by estrogen receptor β (ERβ) and promoted ectopic growth and survival of endometrial tissue. In multiple mouse models that enabled monitoring ERβ activity through a reporter and endometrium-specific ERβ overexpression, pharmacological inhibition, or genetic knockout, increased ERβ activity resulted in larger ectopic endometrial lesions. In both the epithelial and stromal cells of ectopic tissue, ERβ activity promoted proliferation and reduced apoptosis. Analysis of proteins that coimmunoprecipitated with ERβ from ectopic tissue identified proteins associated with extrinsic apoptotic signaling mediated by tumor necrosis factor–α (TNF-α), including caspase 9 and caspase 8, the kinase ASK-1, and the ASK-1 inhibitors STRAP and 14-3-3. Proteins associated with the inflammasome, including caspase 1, NALP3, and interleukin-1β (IL-1β), also coimmunoprecipitated. The interaction of ERβ with ASK-1, STRAP, and 14-3-3 implied that ERβ may limit the activation of ASK-1 in response to TNF-α by inducing the formation of the inhibitory ASK-1, STRAP, 1-3-3 complex. Consistent with this model, the amounts of activating ASK-1 phosphorylation and cytochrome c, a protein involved in apoptosome formation, were reduced in ectopic lesions in ERβ-overexpressing mice compared with ectopic lesions in ERβ-knockout mice. Steroid receptor coactivator 1 (SRC-1) functions with ERβ in the nucleus to regulate transcription but also interacts with caspase 8, inhibiting caspase 8 cleavage and activation. The authors proposed that SRC-1, ERβ, and caspase 8 interacted to prevent caspase 8 cleavage; indeed, less cleaved caspase 8 was present in lesions from the ERβ-overexpressing mice than in lesions from control mice. Although apoptotic caspase activity was reduced by ERβ activity; active caspase 1 and its target, IL-1β, a cytokine that promotes cell adhesion and proliferation, were increased by ERβ activity. Combined inhibition of ERβ and SRC-1 resulted in synergistic reduction in ectopic lesion size in mice with endometriosis. These results suggest that ERβ functions in the cytosol, forming inhibitory complexes that reduce extrinsic apoptosis and forming activating complexes that promote inflammasome-mediated production of IL-1β. Thus, treatments for endometriosis should not only target the transcriptional activities of this steroid receptor.

S. J. Han, S. Y. Jung, S.-P. Wu, S. M. Hawkins, M. J. Park, S. Kyo, J. Qin, J. P. Lydon, S. Y. Tsai, M.-J. Tsai, F. J. DeMayo, B. W. O’Malley, Estrogen receptor β modulates apoptosis complexes and the inflammasome to drive the pathogenesis of endometriosis. Cell 163, 960–974 (2015). [PubMed]