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Biochem Biophys Res Commun. 2019 May 21;513(1):172-178. doi: 10.1016/j.bbrc.2019.03.171. Epub 2019 Apr 2.

Sumoylation of a small isoform of NFATc1 is promoted by PIAS proteins and inhibits transactivation activity.

Author information

1
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
2
Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Yongin, 17035, Republic of Korea.
3
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea; Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, 06351, Republic of Korea. Electronic address: jahn@skku.edu.

Abstract

The NFAT family of transcription factors plays an important role in immune system development and function. NFATc1 and NFATc2 are highly expressed in peripheral T cells, and several isoforms are produced via the use of different promoters and polyadenylation sites. The specific isoforms with relatively long C-termini, NFATc1/C and NFATc2/A, have been shown to be modified by SUMO within their specific C-terminal regions, which regulates NFAT protein localization and transactivation activity. Here, we demonstrate that an isoform NFATc1/A, which has a short C-terminus and does not contain the sumoylation sites found in the long isoforms, is also modified by SUMO. NFATc1/A sumoylation increased with low level expression of SUMO E3 ligases, specifically PIAS1, PIAS3, and PIASy, in co-transfected cells. PIAS3 interacted with NFATc1/A and an active site mutant failed to promote NFATc1/A sumoylation, indicating a role for PIAS3 as a SUMO E3 ligase. A lysine residue at 351 within the central regulatory domain was identified as the major SUMO attachment site in both co-transfection and in vitro assays. Sumoylation of NFATc1/A did not affect nuclear translocation upon ionomycin and phorbol 12-myristate 13-acetate treatment. However, although sumoylation of NFATc1/A slightly increased protein stability, it inhibited transactivation activity for reporter genes driven by promoters containing NFAT sites. Our results indicate that the transactivation activity of NFATc1/A is negatively regulated by PIAS protein-mediated sumoylation, and that SUMO is a general regulator of NFAT family members with either long or short C-termini.

KEYWORDS:

NFATc1/A; PIAS3; SUMO; Transactivation

PMID:
30952432
DOI:
10.1016/j.bbrc.2019.03.171

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