Biology subjects

Re, J.

Publications and source records attributed to Re, J..

5 recordsLinked to original sources

bioRxiv2026

The RLR-MAVS-IRF3 axis activates the IFN pathway to restrict Tonate virus (TONV) infection

Tonate virus (TONV) is a neglected mosquito-borne alphavirus of the Venezuelan equine encephalitis complex associated with febrile illness, encephalitis, and fetal central nervous system abnormalities. Yet, host pathways that sense TONV infection and restrict its replication remain poorly defined. Here, we investigated the interaction between TONV and the type I interferon (IFN-I) system in human cells. We show that TONV infection led to the accumulation of cytosolic double-stranded RNA and a robust IFN response. RIG-I and MDA5 depletion as well as that of MAVS and IRF3 strongly reduced TONV-induced IFN response. Disruption of RIG-I, MDA5, MAVS, or IRF3 resulted in an increase of dsRNA-positive cells and a higher viral RNA accumulation. Finally, we found that treatment with exogenous IFN-I strongly inhibits TONV replication reducing both viral RNA loads and infectious particle production. Thus, together, our results identify the RIG-I/MDA5-MAVS-IRF3 axis as a major pathway sensing TONV infection and establishing an IFN-I-dependent antiviral state, providing the first molecular characterization of TONV innate immune sensing in human cells.

immunology↗

bioRxiv2025

Regulation of lipid metabolism is a primordial function of STING

The stimulator of interferon genes (STING) is a pivotal regulator of type I interferon (IFN) responses. Although the IFN system is confined to vertebrates, STING is present across metazoans and in some unicellular eukaryotes, suggesting involvement in distinct functions prior to vertebrate divergence. We here explored the conservation of STING-mediated regulation of polyunsaturated fatty acid (PUFA) metabolism. We found that tested STING homologs from vertebrates, invertebrates, and unicellular eukaryotes interacted with the fatty acid desaturase 2 (FADS2) rate-limiting enzyme in PUFA metabolism and subsequent functional outputs. The ability to regulate lipid metabolism did not correlate with antiviral activity, suggesting that the cooptation of this metabolic pathway by the IFN-based immune system is independent of STING-associated immune responses. Thus, STING-mediated metabolic regulation is an evolutionarily conserved feature and a primordial STING function.

immunology↗

bioRxiv2025

The Kinase CK1α coordinates Initiation and Termination of the cGAS-STING Pathway

The cGAS-STING pathway is an evolutionarily conserved antimicrobial defense mechanism that senses cytosolic DNA to trigger innate immune responses. cGAS and STING play dual roles in tumorigenesis, promoting antitumor immunity and cell death while fueling tumor growth and metastasis. However, the mechanisms fine-tuning this pathway remain elusive. Using proteomic approaches, we report that Casein Kinase 1 alpha (CK1) operates as a bimodal regulator of the cGAS-STING pathway. CK1 supports optimal DNA sensing by preventing the proteasomal degradation of cGAS driven by the cullin-RING ubiquitin ligase 3 (CRL3). Conversely, CK1 facilitates STING degradation and signaling termination in response to STING agonists, tempering IRF3 activation. Exploiting these counterposing functions, we show that selective degradation of CK1 with molecular-glue degraders impaired the survival of a triple-negative breast cancer cell line with chronic cGAS-STING activation and synergized with a STING agonist to kill acute myeloid leukemia cells. Thus, CK1s dual regulatory role in the cGAS-STING pathway presents a promising target for therapeutic development. TEASERThis study unveils CK1 as a bimodal regulator of the cGAS-STING pathway.

immunology↗

bioRxiv2025

The methyl-CpG-binding protein 2 inhibits cGAS-associated signaling

The detection of cytosolic dsDNA is tightly regulated to avoid pathological inflammatory responses. A major pathway involved in their detection relies on the cyclic GMP-AMP synthase (cGAS) that triggers activation of the Stimulator of interferon genes (STING) which subsequently drives the expression of inflammatory genes and type I Interferons (IFNs). Here, we show that the methyl-CpG-binding protein 2 (MECP2), a major transcriptional regulator, controls dsDNA-associated inflammatory responses. We show that the presence of cytosolic dsDNA promotes MECP2 export from the nucleus to the cytosol where it interacts with dsDNA, dampening cGAS activation. Our data also indicate that MECP2 export from the nucleus partially phenocopies MECP2 deficiency, leading to the expression of inflammatory and interferon stimulated genes, enforcing an antiviral state. Finally, we also show that MECP2 displacement from the nucleus following dsDNA stimulation is sufficient to disrupt its canonical function, leading to the reactivation of otherwise repressed genes, such endogenous retroelements of the Long interspersed nuclear element-1 (LINE-1) family. Re-expression of the latter led to the accumulation of DNA species feeding cGAS-dependent signaling and can be dampened by reverse transcriptase inhibitors. We thus establish a previously unforeseen direct role of MECP2 in the regulation of the breadth and nature of dsDNA-associated inflammatory responses. Furthermore, our results suggest that targeting dsDNA-associated pathways or pharmacological inhibition of LINE-1 may bear therapeutic hopes for Rett syndrome (RTT) patients that present with MECP2 deficiency.

immunology↗

bioRxiv2024

DNA-PK controls cyclic dinucleotide-associated type I Interferon responses

Inflammatory signal termination is critical for the maintenance of homeostasis. Cyclic dinucleotides (CDN) are second messengers that trigger inflammatory responses through the activation of the Stimulator of Interferon Genes (STING) signaling platform. No broad-acting direct regulator of intracellular CDNs has been identified in mammals to date. We show that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a major DNA damage response actor, directly interacts with the intracellular 23-cGAMP CDN through its kinase domain, tempering STING activation. DNA-PKcs also acts on the 33-cGAMP bacterial CDN and pharmacological STING agonists, impacting their bioactivity and ability to mount optimal antiviral responses. STING agonism has been considered as a therapeutic avenue to alleviate immunosuppression in human pathologies. By uncovering DNA-PKcs as a CDN signaling modulator and CDNs as inhibitors of DNA-PKcs kinase activity, we provide critical insights into CDN regulation, with implications for the development of STING-targeting therapeutics.

immunology↗