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The E3 ubiquitin ligase Siah1 regulates adrenal gland organization and aldosterone secretion
Marzia Scortegagna, … , Constantine A. Stratakis, Ze’ev A. Ronai
Marzia Scortegagna, … , Constantine A. Stratakis, Ze’ev A. Ronai
Published December 7, 2017
Citation Information: JCI Insight. 2017;2(23):e97128. https://doi.org/10.1172/jci.insight.97128.
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Research Article Cell biology Endocrinology

The E3 ubiquitin ligase Siah1 regulates adrenal gland organization and aldosterone secretion

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Abstract

Primary and secondary hypertension are major risk factors for cardiovascular disease, the leading cause of death worldwide. Elevated secretion of aldosterone resulting from primary aldosteronism (PA) is a key driver of secondary hypertension. Here, we report an unexpected role for the ubiquitin ligase Siah1 in adrenal gland development and PA. Siah1a–/– mice exhibit altered adrenal gland morphology, as reflected by a diminished X-zone, enlarged medulla, and dysregulated zonation of the glomerulosa as well as increased aldosterone levels and aldosterone target gene expression and reduced plasma potassium levels. Genes involved in catecholamine biosynthesis and cAMP signaling are upregulated in the adrenal glands of Siah1a–/– mice, while genes related to retinoic acid signaling and cholesterol biosynthesis are downregulated. Loss of Siah1 leads to increased expression of the Siah1 substrate PIAS1, an E3 SUMO protein ligase implicated in the suppression of LXR, a key regulator of cholesterol levels in the adrenal gland. In addition, SIAH1 sequence variants were identified in patients with PA; such variants impaired SIAH1 ubiquitin ligase activity, resulting in elevated PIAS1 expression. These data identify a role for the Siah1-PIAS1 axis in adrenal gland organization and function and point to possible therapeutic targets for hyperaldosteronism.

Authors

Marzia Scortegagna, Annabel Berthon, Nikolaos Settas, Andreas Giannakou, Guillermina Garcia, Jian-Liang Li, Brian James, Robert C. Liddington, José G. Vilches-Moure, Constantine A. Stratakis, Ze’ev A. Ronai

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Figure 5

Downregulation of LXR/RXR and FXR/RXR expression and cholesterol biosynthesis correlates with induction of PIAS1 SUMO E3 ligase protein in the adrenal glands of Siah1a–/– mice.

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Downregulation of LXR/RXR and FXR/RXR expression and cholesterol biosynt...
(A) Heatmap of RNA-seq data from the adrenal glands of female and male WT and Siah1a KO mice, showing the top canonical pathways upregulated and downregulated in Siah1a KO mice. Selection criteria were P ≤ 0.05 and ≥2-fold change in expression. (B) PIAS1 staining (red) in sections of adrenal glands from 21-day-old WT and Siah1a KO mice. Scale bar: 100 μm. Original magnification, ×3 (insets). Images shown are representative of images from 4 different mice per group. (C) Western blot analysis of PIAS1 and tubulin expression in protein lysates of pooled adrenal glands from 3 WT, 3 Siah1a+/–, and 3 Siah1a–/– mice. (D) Siah1, PIAS1, and actin expression in 293T cells transfected with PIAS1 alone and PIAS1 plus Siah1. Cells were treated with the protein synthesis inhibitor cycloheximide (CHX) for the indicated times. Dashed lines denote the different degradation rate of PIAS1 alone versus PIAS1 coexpressed with Siah1. The graph shows quantification of PIAS1 degradation from 4 independent experiments. *P < 0.05, **P < 0.005, compared with PIAS1 alone. Data are shown as mean ± SEM. Statistical analysis was performed using t test.

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