GPLD1-mediated regulation of the type I interferon-induced signaling pathway and antiviral activity.

Abstract

Glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) is traditionally known as a secreted enzyme that sheds glycosylphosphatidylinositol (GPI)-anchored proteins. Emerging evidence suggests its involvement in immune modulation. In this study, we report a non-canonical intracellular function of GPLD1 in potentiating IFN-I-mediated antiviral signaling. Mechanistically, GPLD1 physically interacts with signal transducer and activator of transcription 2 (STAT2) and competitively blocks its interaction with protein-tyrosine phosphatase 1B (PTP1B), a bona fide phosphatase that directly dephosphorylates STAT2 at Tyr690. By shielding STAT2 from PTP1B-mediated dephosphorylation, GPLD1 sustains STAT2 phosphorylation and facilitates time-dependent STAT2 nuclear translocation, thereby amplifying interferon-stimulated gene (ISG) expression and antiviral responses. Collectively, we identify a novel molecular mechanism by which GPLD1 regulates the IFN-I signaling pathway, providing a potential therapeutic target for the development of future antiviral strategies.