E3 ubiquitin ligase RNF31 cooperates with DAX-1 in transcriptional repression of steroidogenesis.
Genetic and experimental evidence points to a critical involvement of the atypical mammalian orphan receptor DAX-1 in reproductive development and steroidogenesis. Unlike conventional nuclear receptors, DAX-1 appears not to function as a DNA-bound transcription factor. Instead, it has acquired the capability to act as a transcriptional corepressor of steroidogenic factor 1 (SF-1). The interplay of DAX-1 and SF-1 is considered a central, presumably ligand-independent element of adrenogonadal development and function that requires tight regulation. This raises a substantial interest in identifying its modulators and the regulatory signals involved. Here, we uncover molecular mechanisms that link DAX-1 to the ubiquitin modification system via functional interaction with the E3 ubiquitin ligase RNF31. We demonstrate that RNF31 is coexpressed with DAX-1 in steroidogenic tissues and participates in repressing steroidogenic gene expression. We provide evidence for the in vivo existence of a corepressor complex containing RNF31 and DAX-1 at the promoters of the StAR and CYP19 genes. Our data suggest that RNF31 functions to stabilize DAX-1, which might be linked to DAX-1 monoubiquitination. In conclusion, RNF31 appears to be required for DAX-1 to repress transcription, provides means to regulate DAX-1 in ligand-independent ways, and emerges as a relevant coregulator of steroidogenic pathways governing physiology and disease.
Ehrlund
Anna
A
Department of Biosciences and Nutrition, Karolinska Institutet, S-14157 Huddinge/Stockholm, Sweden.
Anthonisen
Elin Holter
EH
Gustafsson
Nina
N
Venteclef
Nicolas
N
Robertson Remen
Kirsten
K
Damdimopoulos
Anastasios E
AE
Galeeva
Anastasia
A
Pelto-Huikko
Markku
M
Lalli
Enzo
E
Steffensen
Knut R
KR
Gustafsson
Jan-Ake
JA
Treuter
Eckardt
E
D045744:Cell Line, Tumor; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D006801:Humans; D055550:Protein Stability; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D054339:Steroidogenic Factor 1 / Q000235:genetics*; D013256:Steroids / Q000096:biosynthesis*; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D013256:Steroids; D044767:Ubiquitin-Protein Ligases