STAT3 Cooperates With Phospholipid Scramblase 2 to Suppress Type I Interferon Response

Frontiers in Immunology
Ming-Hsun Tsai, Chien-Kuo Lee

Abstract

Type I interferon (IFN-I) is a pluripotent cytokine that modulates innate and adaptive immunity. We have previously shown that STAT3 suppresses IFN-I response in a manner dependent on its N-terminal domain (NTD), but independent of its DNA-binding and transactivation ability. Using the yeast two-hybrid system, we have identified phospholipid scramblase 2 (PLSCR2) as a STAT3 NTD-binding partner and a suppressor of IFN-I response. Overexpression of PLSCR2 attenuates ISRE-driven reporter activity, which is further aggravated by co-expression of STAT3. Moreover, PLSCR2 deficiency enhances IFN-I-induced gene expression and antiviral activity without affecting the activation or nuclear translocation of STAT1 and STAT2 or the assembly of ISGF3 complex. Instead, PLSCR2 impedes promoter occupancy by ISGF3, an effect further intensified by the presence of STAT3. Moreover, palmitoylation of PLSCR2 is required for its binding to STAT3 and for this suppressive activity. In addition to STAT3, PLSCR2 also interacts with STAT2, which facilitates the suppressive effect on ISGF3-mediated transcriptional activity. Together, these results define the role of a novel STAT3-PLSCR2 axis in fine-tuning IFN-I response.

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Citations

Oct 3, 2019·International Journal of Molecular Sciences·Huanru WangZhiwei Wu
Jan 24, 2019·Frontiers in Immunology·Hao-Sen Chiang, Helene Minyi Liu
Jul 12, 2019·Frontiers in Immunology·Ming-Hsun TsaiChien-Kuo Lee
Nov 16, 2019·PLoS Biology·Toshihiko KobayashiNoriko Toyama-Sorimachi
Sep 26, 2020·Molecular Cancer·Sailan ZouXianghui Fu
Jun 14, 2019·Frontiers in Immunology·Philipp M HagemannZane Orinska
Aug 28, 2020·Journal of Virology·Angela R Harrison, Gregory W Moseley
Sep 20, 2021·Journal of Molecular Biology·Michael J McFaddenStacy M Horner

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Methods Mentioned

BETA
nuclear translocation
transfection
immunoprecipitation
PCR
Assay
confocal microscopy
ChIP
X-ray
Two-Hybrid
co-IP

Software Mentioned

ImageJ

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