SUMOylation of the Forkhead transcription factor FOXL2 promotes its stabilization/activation through transient recruitment to PML bodies.
BACKGROUND
FOXL2 is a transcription factor essential for ovarian development and maintenance. It is mutated in the genetic condition called Blepharophimosis Ptosis Epicantus inversus Syndrome (BPES) and in cases of isolated premature ovarian failure. We and others have previously shown that FOXL2 undergoes several post-translational modifications.


RESULTS
Here, using cells in culture, we show that interference with FOXL2 SUMOylation leads to a robust inhibition of its transactivation ability, which correlates with a decreased stability. Interestingly, FOXL2 SUMOylation promotes its transient recruitment to subnuclear structures that we demonstrate to be PML (Promyelocytic Leukemia) Nuclear Bodies. Since PML bodies are known to be sites where post-translational modifications of nuclear factors take place, we used tandem mass spectrometry to identify new post-translational modifications of FOXL2. Specifically, we detected four phosphorylated, one sulfated and three acetylated sites.


CONCLUSIONS
By analogy with other transcription factors, we propose that PML Nuclear Bodies might transiently recruit FOXL2 to the vicinity of locally concentrated enzymes that could be involved in the post-translational maturation of FOXL2. FOXL2 acetylation, sulfation, phosphorylation as well as other modifications yet to be discovered might alter the transactivation capacity of FOXL2 and/or its stability, thus modulating its global intracellular activity.
Programme de Pathologie Moléculaire et Cellulaire, Institut Jacques Monod, UMR 7592 CNRS-Université Paris Diderot, Paris, France.
Adrien
A
Georges
Bérénice A
BA
Benayoun
Mara
M
Marongiu
Aurélie
A
Dipietromaria
David
D
L'Hôte
Anne-Laure
AL
Todeschini
Jana
J
Auer
Laura
L
Crisponi
Reiner A
RA
Veitia
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism*; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D021381:Protein Transport; D058207:Sumoylation; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics*
C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D050505:Mutant Proteins; D010455:Peptides