Editors' ChoiceNuclear Receptors

Flies Reveal New Nuclear Receptor Signaling Mechanism

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Science's STKE  17 Jun 2003:
Vol. 2003, Issue 187, pp. tw226-TW226
DOI: 10.1126/stke.2003.187.tw226

Ecdysteroids are hormones with important roles in regulating development and metamorphosis in insects. Like mammalian steroid hormones, they act to regulate transcription through a nuclear receptor, the ecdysone receptor (EcR). The EcR forms heterodimers with Ultraspiracle (USP), which is related to another nuclear receptor family member, the vertebrate retinoid X receptor (RXR). However, the EcR appears not to mediate all effects of ecdysone and related ecdysteroids found in insect hemolymph. Baker et al. therefore examined the function of DHR38, an insect nuclear receptor that heterodimerizes with USP. The authors constructed a reporter system that used the better-characterized RXR as a partner in place of USP and showed that transcriptional activity of the complex was activated in response to various ecdysteroids. Activation of complexes of DHR38 with RXR required ligand-induced activation of both receptors, and the same appeared to be true of complexes with USP. Particularly surprising were experiments showing that DHR38, although responsive to ecdysteroids, appears not to bind the ligands directly. An X-ray crystal structure of the protein confirmed that the ligand-binding pocket and the coactivator binding sites normally conserved in nuclear receptors are unlikely to function in DHR38. The authors speculate that a cofactor acting with the receptors at sites of transcriptional activation might confer sensitivity to ecdysteroids. Because DHR38 is related to a subfamily of mammalian orphan nuclear receptors (the NGFI-B subfamily), the new paradigm for activation revealed by DHR38 in flies may be relevant to signaling by vertebrate nuclear receptors as well.

K. D. Baker, L. M. Shewchuk, T. Kozlova, M. Makishima, A. Hassell, B. Wisely, J. A. Caravella, M. H. Lambert, J. L. Reinking, H. Krause, C. S. Thummel, T. M. Willson, D. J. Mangelsdorf, The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway. Cell 113, 731-742 (2003). [Online Journal]

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