Abstract
ABSTRACTIt has been shown that the nucleoporin ALADIN plays a significant role in the redox homeostasis of the cell, but its function in steroidogenesis contributing to adrenal atrophy in triple A syndrome remains largely unknown. In an attempt to identify new interaction partners of ALADIN, co-immunoprecipitation followed by proteome analysis was conducted in different expression models using the human adrenocortical tumour cell line NCI-H295R. Our results suggest an interaction of ALADIN with the microsomal protein PGRMC2. PGRMC2 is shown to be activity regulator of CYP P450 enzymes and, therefore, to be a possible target for adrenal dysregulation in triple A syndrome. We show that there is a sexual dimorphism regarding the expression of Pgrmc2 in adrenals and gonads of wild-type (WT) and Aaas knock-out (KO) mice. Female Aaas KO mice are sterile due to delayed oocyte maturation and meiotic spindle assembly. A participation in meiotic spindle assembly confirms the recently investigated involvement of ALADIN in mitosis and emphasises an interaction with PGRMC2 which is a regulator of the cell cycle. By identification of a novel interaction partner of ALADIN, we provide novel aspects for future research of the function of ALADIN during cell cycle and for new insights into the pathogenesis of triple A syndrome.
Highlights
Triple A syndrome (MIM#231550) is an autosomal recessive disorder characterised by three distinct symptoms: ACTH-resistant adrenal insufficiency, oesophageal achalasia and absent tear production in combination with progressive neurological impairment (Allgrove et al, 1978)
We found that Pgrmc2 displayed a sexual dimorphism in female and male WT and Aaas KO mice: the expression in testes was significantly higher independent of genotype compared to female ovaries, in female KO adrenals the expression was significantly higher compared to male KO adrenals (Fig. 5A)
The exact role of the nucleoporin ALADIN at the NPC and its involvement in steroidogenesis leading to the characteristic adrenal atrophy in triple A syndrome remains largely unknown
Summary
Triple A syndrome (MIM#231550) is an autosomal recessive disorder characterised by three distinct symptoms: ACTH-resistant adrenal insufficiency, oesophageal achalasia and absent tear production (alacrima) in combination with progressive neurological impairment (Allgrove et al, 1978). ALADIN is a scaffold nucleoporin (NUP) anchored within the nuclear pore complex (NPC) by the transmembrane NUP NDC1 [nuclear division cycle 1 homologue (S. cerevisiae)] ALADIN presents enhanced protein levels in neuroendocrine and gastrointestinal tissue; structures which are predominately affected in triple A patients (Handschug et al, 2001).
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