Selective SUMO modification of cAMP-specific phosphodiesterase-4D5 (PDE4D5) regulates the functional consequences of phosphorylation by PKA and ERK.

Xiang Li , Suryakiran Vadrevu , Allan John Dunlop , Jon Day , Noopur Advant , Jessica Troeger , Enno Klussmann , Ellis G Jaffray , Ronald T. Hay , David R Adams , Miles Douglas Houslay , George S. Baillie (1)

1 Biochemistry and Molecular Biology

Enzymes from the PDE4 cAMP-specific phosphodiesterase family are crucial for the maintenance of compartmentalized cAMP responses in many cell types. Regulation of phosphodiesterase (PDE) activity can be achieved via post-translational modification such as phosphorylation by ERK MAP kinases and Protein Kinase A. In the present study we report for the first time that PDE4 isoforms from the PDE4A and PDE4D sub-families can be selectively modified by the small ubiquitin related modifier, SUMO. We identify a single SUMO site within a consensus tetrapeptide motif, y-K-X-E (y represents a hydrophobic residue), which lies in the catalytic unit of these enzymes. SUMO modification of PDE4 at this site was observed upon overexpression of the SUMO E3 ligase, PIASy in HEK cells and we identify PIASy as a novel binding partner for long PDE4 isoforms. Site directed mutagenesis of the acceptor lysine ablated conjugation of PDE4 with SUMO, suggesting the presence of a single SUMO site in the first sub-domain of the conserved PDE4 catalytic unit. This observation was supported by both cell-free, in vitro SUMOylation assays and by analysis of SUMOylated spot-immobilised peptide arrays. SUMO modification of long PDE4 isoforms serves to augment their activation by PKA phosphorylation and repress their inhibition by ERK phosphorylation. Following ligation of b-adrenergic receptors, SUMOylation of PDE4 isoforms sufficiently amplified PKA-stimulated PDE4 activity to reduce markedly the PKA phosphorylation status of the b2-adrenergic receptor. These data highlight a new means whereby cells might achieve the selective regulation of the activity of cAMP specific PDE4 phosphodiesterases.

Mots clés: Life Sciences

Xiang Li, Suryakiran Vadrevu, Allan John Dunlop, Jon Day, Noopur Advant, et al.. Selective SUMO modification of cAMP-specific phosphodiesterase-4D5 (PDE4D5) regulates the functional consequences of phosphorylation by PKA and ERK.. Biochemical Journal, 2010, 428 (1), pp.55-65. ⟨10.1042/BJ20091672⟩. ⟨hal-00479279⟩