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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 6

Reduced activity of Siah1 I251L and increased PIAS1 expression in a patient with primary aldosteronism.

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Reduced activity of Siah1 I251L and increased PIAS1 expression in a pati...
(A) Cartoon representation of Siah1 surrounding the I151L mutation site (yellow sticks, blue label) that lies on a “helix-turn-helix” element that connects the dimer interface to the linker between the 2 Zn fingers (indicated by dashed black double-headed arrow). Ile151 is partly buried but also forms part of a prominent pocket (“D”; brown dashed circle). Loss-of-function mutation sites are colored red, and a red circle emphasizes how they cluster across the SBD dimer interface (part of second SBD is in gray). Three crystal forms are overlaid (see Methods and Results) to demonstrate conformational heterogeneity in the second Zn finger (ZnF-2). For clarity, ZnF-2 is represented by a single helix (each structure is labeled by its PDB code, see Methods), but the motion is simple rigid-body rotation about the axis labeled “R,” circled in orange. The RING domain is N-terminal to ZnF-2, and its structure has not been determined. (B) Western blot analysis of PIAS1 expression in 293T cells transfected with PIAS1-V5 alone or in combination with either Siah1-myc or Siah1-I251L-myc. A cycloheximide (CHX) chase was performed for the indicated times. Blots were probed with antibodies against V5 or myc. Tubulin served as a loading control. Dashed lines denote the different degradation rate of PIAS1 coexpressed with WT Siah1 versus PIAS1 coexpressed with Siah1-I251L. The graph shows quantification of PIAS1 degradation from 5 independent experiments. *P < 0.05, compared with Siah1 + PIAS1. (C) Immunohistochemical staining of PIAS1 in adrenal gland sections of 2 patients with primary aldosteronism harboring either I251L or R29I. The line represents the delimitation between the surrounding tissue (S) and the tumoral tissue (T). Data are shown as mean ± SEM. Statistical analysis was performed using t test. Scale bar: 50 μm

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