ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling

Area of Science:

• Immunology
• Cell Biology
• Genetics

Background:

• Type I interferon (IFN) signaling is critical for immunity but requires strict regulation.
• The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway initiates IFN responses upon DNA detection.
• STING trafficking and degradation are key control points for terminating IFN signaling.

Purpose of the Study:

• To identify novel regulators of the cGAS-STING pathway.
• To investigate the role of ADP-ribosylation factor 1 (ARF1) in IFN signaling.
• To characterize a newly identified interferonopathy linked to ARF1 mutations.

Main Methods:

• Analysis of patient-derived cells with heterozygous ARF1 missense mutations.
• Cellular assays to assess cGAS-STING pathway activation and IFN-stimulated gene expression.
• Investigation of STING trafficking, mitochondrial morphology, and retrograde transport.

Main Results:

• Heterozygous ARF1 missense mutations cause a novel type I interferonopathy.
• GTPase-defective ARF1 enhances cGAS-STING dependent IFN signaling.
• Mutated ARF1 disrupts mitochondrial integrity, leading to aberrant DNA release and STING accumulation at the Golgi/ERGIC.

Conclusions:

• ARF1 acts as a crucial negative regulator of cGAS-STING signaling.
• ARF1 mutations impair mitochondrial homeostasis and STING recycling, dysregulating IFN responses.
• ARF1 has a dual role in maintaining cGAS-STING pathway balance through mitochondrial integrity and STING recycling.