Mechanisms of Differential Signal Transduction by IFNLR1 Variants.

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Interferon lambda (IFNL) binds the interferon lambda receptor-1 (IFNLR1) and IL10RB receptor complex to trigger interferon-stimulated genes (ISGs) and antiviral immunity.
• Distinct IFNLR1 splice variants influence gene expression and HBV replication in hepatocytes.
• This study investigates the signaling mechanisms of a canonical IFNLR1 (variant 1) versus a noncanonical variant (variant 2) lacking key JAK1-interacting motifs.

Purpose of the Study:

• To elucidate the molecular mechanisms of signal transduction by two distinct IFNLR1 variants.
• To compare the functional consequences of canonical versus noncanonical IFNLR1 variants on IFNL-induced cellular responses.
• To understand how IFNLR1 variants affect JAK-STAT pathway activation and ISG expression.

Main Methods:

• Utilized HEK293T cells and wild-type (WT) and IFNLR1 knock-out (KO) iHeps expressing doxycycline-inducible IFNLR1 variants.
• Assessed cellular responses via Duolink proximity ligation assay, ImageStream flow cytometry, and western blotting for JAK-STAT proteins.
• Analyzed susceptibility to JAK1/TYK2 inhibitors and performed gene expression profiling.

Main Results:

• Both IFNLR1 variants colocalized with IL10RB, but variant 1 showed faster and greater internalization.
• Variant 1 expression led to enhanced STAT1/STAT2 phosphorylation and broader ISG induction compared to variant 2.
• IFNLR1 variants differentially influenced TYK2-dependent ISG expression, impacting antiviral and proinflammatory responses.

Conclusions:

• IFNLR1 variants differentially utilize signaling mediators, modulating IFNL-induced gene expression patterns.
• These variants play a role in regulating the interferon signaling pathway.
• Understanding these variant-specific mechanisms is crucial for comprehending antiviral immunity and potential therapeutic strategies.