PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation

Area of Science:

• Molecular Biology
• Immunology
• RNA Biology

Background:

• Pseudouridine synthases (PUSs) modify uridine to pseudouridine (Ψ), impacting RNA function.
• The role of PUSs in stress adaptation and innate immunity is largely unknown.
• PUS10's specific function in these processes requires further investigation.

Purpose of the Study:

• To investigate the role of PUS10 in intracellular innate immunity.
• To understand how PUS10 loss affects gene expression and immune signaling.
• To explore the link between PUS10 dysregulation and autoimmune diseases.

Main Methods:

• Utilized Pus10 knockout mice to study immune responses in vivo.
• Analyzed changes in tRNA-derived small RNAs (tdRs) abundance and their impact on translation.
• Investigated the accumulation of RNA-DNA hybrids and their potential activation of the cGAS-STING pathway.

Main Results:

• Pus10 knockout mice exhibited cell-intrinsic upregulation of interferon (IFN) signaling, leading to inflammation resistance.
• Pus10 loss altered tdR abundance, affecting translation and endogenous retroelements expression.
• Proinflammatory RNA-DNA hybrids accumulated, potentially activating the cGAS-STING pathway.

Conclusions:

• PUS10 plays an unconventional role in modulating intracellular innate immunity.
• Altered tdRs and RNA-DNA hybrids in Pus10-deficient cells contribute to a pro-inflammatory state.
• PUS10 dysregulation is linked to human autoimmune disorders, identifying it as a viral mimicry modulator relevant to immune homeostasis.