ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2006) 12 S10

Repression of NR5A nuclear receptors by SUMO and DEAD-box proteins

Y Wang1, Y Sampathkumar1, DN Peiris1, RA Manan1, LA Lebedeva2, M Suzawa2, SA Wadekar2, M Desclozeaux2, HA Ingraham2 & MB Lee1

1National University of Singapore, Singapore, Singapore; 2University of California, San Francisco, United States.

The Nuclear Receptor Subfamily 5A member, Steroidogenic Factor 1 (SF-1, Ad4BP, NR5A1), is critical for steroidogenesis, stress responses, sexual differentiation and body weight regulation in mice. Patients with rare mutations in SF-1 have confirmed its role in male sexual differentiation and adrenal response to physiological stress in humans. In contrast, Liver Receptor Homologue 1 (LRH-1, FTF, CPF, NR5A2) is involved in endoderm development, bile acid and lipid metabolism and intestinal epithelial proliferation. Structural studies have implicated phospholipids as potential ligands for NR5A receptors, but true endogenous ligands remain to be identified. Functional studies, however, suggest that these receptors are constitutively active as monomers and are regulated by ligand-independent mechanisms such as post-translational phosphorylation, acetylation and sumoylation. Unlike phosphorylation which activates the receptor, sumoylation in the distal hinge domain strongly repressed SF-1 transcriptional activity. The mechanism for this repression involved direct interaction between sumoylated SF-1 and the DEAD-box RNA helicase DP103, a known repressor of SF-1. Furthermore, DP103 synergized specifically with the E3 SUMO ligases PIAS-y and PIAS-x-alpha to promote PIAS-dependent SF-1 sumoylation and relocalization in cellular systems. Deletion analysis identified a domain within DP103 that was sufficient to direct and promote PIAS-specific SF-1 sumoylation. Analysis of SF-1-expressing cell lines revealed that endogenous SF-1 was sumoylated and confirmed co-expression of DP103 and PIAS proteins with SF-1. Collectively, these data suggest a multi-functional and direct role for DEAD-box RNA helicases in SUMO-mediated transcriptional repression. Ongoing studies will clarify the structural, mechanistic and developmental relationships between the helicase and its cognate receptor.

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