MAPK-induced Ser(727) phosphorylation promotes SUMOylation of STAT1

作者：Vanhatupa Sari; Ungureanu Daniela; Paakkunainen Maija; Silvennoinen Olli^*

来源：Biochemical Journal, 2008, 409(1): 179-185.

DOI：10.1042/BJ20070620

• mitogen-activated protein kinase (MAPK)
• signal transducer and activator of transcription (STAT)
• protein inhibitor of activated STAT1 (PIAS1)
• Ser(727) phosphorylation
• small ubiquitin-related modifier (SUMO)
• transcription factor

STAT1 (signal transducer and activator of transcription 1) is a critical mediator of IFN-gamma (interferon-gamma)-induced gene responses, and its function is regulated through phosphorylation of Tyr(701) and Ser(727). MAPK (mitogen-activated protein kinase) pathways mediate phosphorylation of Ser(727) in response to microbial infections, stress stimuli and growth factors. Recently, STAT1 was found to become modified by PIAS (protein inhibitor of activated STAT)-mediated SUMO-1 (small ubiquitin-related modifier-1) conjugation at Lys(703), but the regulation of this modification is largely unknown. Here, we have investigated the role of MAPK-induced Ser(727) phosphorylation in regulation of STAT1 SUMOylation. Activation of the p38MAPK pathway by upstream activating kinase, MKK6 (MAPK kinase-6) or osmotic stress enhanced the SUMOylation of STAT1, which was counteracted by the p38MAPK inhibitor SB202190 or by dominant-negative p38MAPK. Activation of the ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway by Raf-1 also enhanced Ser(727) phosphorylation and SUMOylation of STAT1, and this induction was counteracted by PD98059 inhibitor. Mutation of Ser(727) to alanine abolished the p38MAPK-induced SUMOylation. Furthermore, S727D and S727E mutations, which mimic the phosphorylation of Ser(727), enhanced the basal SUMOylation of STAT1 and interaction between PIAS1 and STAT1. Taken together, these results identify Ser(727) phosphorylation as a regulator of STAT1 SUMOylation and highlight the central role of Ser(727) in coordination of STAT1 functions in cellular responses.

• 出版日期2008-1-1
• 单位河北医科大学