MAPK-induced Ser727 phosphorylation promotes sumoylation of STAT1

Sari Vanhatupa , Daniela Ungureanu , Maija Paakkunainen , Olli Silvennoinen (1)

1 Molecular Immunology

Signal transducer and activator of transcription 1 (STAT1) is a critical mediator of interferon-γ (IFN-γ)-induced gene responses, and its function is regulated through phoshorylation of Tyr701 and Ser727. Mitogen-activated protein kinase (MAPK) pathways mediate phosphorylation of Ser727 in response to microbial infections, stress stimuli and growth factors. Recently, STAT1 was found to become modified by PIAS mediated SUMO-1 conjugation at Lys703, but the regulation of this modification is largely unknown. Here, we have investigated the role of MAPK-induced Ser727 phosphorylation in regulation of STAT1 sumoylation. Activation of p38MAPK pathway by upstream activating kinase, mitogen-activated protein kinase kinase-6 (MKK6) or osmotic stress, enhanced sumoylation of STAT1, which was counteracted by the p38MAPK inhibitor SB202190 or by dominant negative p38MAPK. Activation of extracellular signal regulated kinase (ERK) 1/2 pathway by Raf-1 also enhanced Ser727 phosphorylation and sumoylation of STAT1, and this induction was counteracted by PD98059 inhibitor. Mutation of Ser727 to Ala abolished the p38MAPK-induced sumoylation. Furthermore, Ser727Asp and Ser727Glu mutations, that mimic the phosphorylation of Ser727, enhanced the basal sumoylation of STAT1, and interaction between PIAS1 and STAT1. Taken together, these results identify Ser727 phosphorylation as a regulator of STAT1 sumoylation, and highlight the central role of Ser727 in co-ordination of STAT1 functions in cellular responses.

Mots clés: Life Sciences

Sari Vanhatupa, Daniela Ungureanu, Maija Paakkunainen, Olli Silvennoinen. MAPK-induced Ser727 phosphorylation promotes sumoylation of STAT1. Biochemical Journal, 2007, 409 (1), pp.179-185. ⟨10.1042/BJ20070620⟩. ⟨hal-00478798⟩