Lysosomal control of type I interferon induction via Ragulator-Rag complex [ATAC-seq]

The type I interferon (IFN) response is a pivotal transcription program in the host innate immunity against infectious viruses that induces a multitude of interferon-stimulated genes (ISGs) to antagonize every stage of viral replication. Aberrant IFN response often leads to enhanced viral susceptibility or autoimmune conditions. Accordingly, type I IFN induction is tightly regulated from viral recognition to signaling propagation and transcriptional activation to cytokine production. Lysosomes, which are essential organelles for cellular homeostasis and metabolic signaling, play an evolutionarily conserved role in viral clearance. Through their degradative capacity and recycling function, lysosomes facilitate the containment and destruction of viral particles or debris delivered via endocytic, autophagic, and phagocytic routes. Despite the central role of lysosomes in virus-host interactions, it remains unclear whether type I IFN induction requires direct lysosomal input. Here, we identified the lysosomal scaffold Ragulator as crucial for IFN-β transcriptional activation through an antiviral screen using a GFP-expressing Influenza A virus as a readout. Independent of their known roles in mTORC1 regulation, the Ragulator-dependent antiviral response requires downstream heterodimeric Rag GTPases that alter their nucleotide-loading states to establish the IFN-I gene signature. Depleting Ragulator or Rag GTPases causes exhaustion of a regulatory pool of interferon-regulator factors (IRFs), leading to abrogated Ifnb1 transcription, IFN-β secretion, and ISG response, thereby enhancing susceptibility to viral infections both in cells and in vivo. Thus, our findings reveal a new role for lysosomes in the nuclear transcription of antiviral innate immunity.