# The lysosomal LAMTOR-Rag complex functions as a checkpoint for antiviral interferon production

## TL;DR

The lysosomal LAMTOR-Rag complex acts as a nutrient-sensitive checkpoint for antiviral interferon production, linking metabolism and immunity.

## Contribution

The study identifies a lysosome-specific checkpoint for IFN-β production that operates independently of mTORC1.

## Key findings

- LAMTOR-Rag complex is essential for IFN-β production across multiple PRR signaling pathways.
- Rag GTPase regulates IRF-5/7 and p38 MAPK recruitment to lysosomes, stabilizing Ifnb1 mRNA.
- Disruption of the LAMTOR-Rag-FLCN-p38 axis impairs antiviral responses in vitro and in vivo.

## Abstract

Lysosomes are emerging as important signaling hubs for antiviral defense, yet how they enable type I interferon (IFN-β) production is unclear. Here, we identify an evolutionarily repurposed lysosomal pathway, centered on the LAMTOR-Rag GTPase complex, that governs IFN-β production through dual transcriptional and post-transcriptional regulation. Genetic ablation of LAMTOR or Rag GTPases in macrophages abolishes IFN-β responses despite intact pattern recognition receptor (PRR) signaling, uncovering a lysosome-specific checkpoint essential for antiviral immunity. Mechanistically, Rag GTPase activity controls IRF expression to prime IFN transcription, while upon PRR stimulation, the tumor suppressor FLCN recruits p38 MAPK to lysosomes, where Rag-dependent p38 phosphorylation stabilizes Ifnb1 mRNA. Nutrient availability dynamically modulates Rag nucleotide states and thereby its activation, linking IFN production to metabolic capacity. Notably, this checkpoint operates independently of mTORC1, illustrating how an ancient nutrient-sensing module has been co-opted for immune regulation. Disruption of the LAMTOR-Rag-FLCN-p38 axis impairs IFN induction in vitro and antiviral responses in vivo, underscoring its physiological significance. Our findings support the role of the lysosome as a central signaling hub integrating metabolic and immune cues, suggesting future directions for potential therapeutic strategies against viral infections.

Lysosomal membrane-recruited factors, including the Ragulator-Rag-mTORC1 pathway, regulate innate immune response to pathogen infection. This study reveals the lysosomal LAMTOR-Rag GTPase axis as a nutrient-sensitive checkpoint for type I interferon production, coordinating transcriptional priming and mRNA stabilization to mount antiviral responses independently of mTORC1.

Lysosomal LAMTOR-Rag complex is essential for IFN-β production across multiple pattern recognition receptor (PRR) signaling pathways.Rag GTPase nucleotide states regulate IRF-5/7 expression and p38 MAPK activation and recruitment to the lysosome.Lysosome-localized p38 MAPK promotes stability of Ifnb1 mRNA.Disruption of this pathway impairs antiviral defense in cells and in vivo.

Lysosomal LAMTOR-Rag complex is essential for IFN-β production across multiple pattern recognition receptor (PRR) signaling pathways.

Rag GTPase nucleotide states regulate IRF-5/7 expression and p38 MAPK activation and recruitment to the lysosome.

Lysosome-localized p38 MAPK promotes stability of Ifnb1 mRNA.

Disruption of this pathway impairs antiviral defense in cells and in vivo.

An mTORC1-independent function of the lysosomal LAMTOR-Rag complex regulates type I interferon production and antiviral defense in a nutrient-sensitive manner.