SUMO modification of repression domains modulates function of nuclear receptor 5A1 (steroidogenic factor-1)

Abstract

Steroidogenic factor 1 (SF-1 or NR5A1), is a Ftz-F1 member of the nuclear receptor superfamily that plays essential roles in endocrine development, steroidogenesis, and gonad differentiation. We investigated modifications that control SF-1 function and found that SF-1 could be conjugated by SUMO-1 both in vitro and in vivo. SF-1 was modified predominantly at Lys(194) and much less at Lys(119) when free SUMO-1 was supplied. Mutations of Lys(194) and Lys(119) enhanced transcriptional activity of SF-1, although the DNA binding activity of SF-1 was not affected. Sequences around Lys(194) and Lys(119) both repressed transcription intrinsically. The Lys(194) motif repressed transcription more efficiently than the Lys(119) domain, consistent with its ability to be a better substrate for SUMO conjugation. Thus, SUMO modification of SF-1 correlates with transcriptional repression. Wild-type but not conjugation-deficient SF-1 was localized at the nuclear speckles together with SUMO-1. Thus, SUMO-1 conjugation could also target SF-1 into nuclear speckles. Collectively, these results suggest that SUMO modification at the repression domains targets SF-1 to nuclear speckles; this could be an important mechanism by which SF-1 is regulated.