STING inhibits LINE-1 retrotransposition through sorting ORF1p to lysosomes for degradation

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• The stimulator of interferon genes (STING) protein is a key regulator of innate immunity, primarily known for its role in interferon and inflammatory responses.
• STING also possesses functions beyond interferon induction, suggesting broader roles in cellular homeostasis.
• Long interspersed nuclear element 1 (LINE-1) is the sole active autonomous retrotransposable element in the human genome, and its uncontrolled transposition can lead to genetic instability and disease.

Purpose of the Study:

• To investigate the role of STING in the regulation of LINE-1 retrotransposition.
• To elucidate the mechanism by which STING restricts LINE-1 mobilization, particularly independent of cGAS and interferon pathways.

Main Methods:

• Investigated STING's interaction with LINE-1 components.
• Utilized cellular localization studies to track the STING-LINE-1 complex.
• Examined the requirement of STING dimerization for LINE-1 restriction.
• Assessed the role of cellular compartments like ERGIC and lysosomes in the process.

Main Results:

• STING restricts LINE-1 retrotransposition through an interferon-independent mechanism.
• STING's inhibitory function on LINE-1 requires its dimerization.
• STING directly interacts with LINE-1 ORF1p.
• The STING-LINE-1 complex is trafficked to the ER-Golgi intermediate compartment (ERGIC) and Golgi, subsequently sorted to Rab7-positive lysosomes for degradation.

Conclusions:

• STING plays a novel role in maintaining host genome integrity by suppressing LINE-1 retrotransposition.
• This STING-mediated restriction of LINE-1 is independent of cGAS and interferon induction.
• The findings reveal a new pathway for controlling mobile genetic elements and preventing associated diseases.