Biology subjects

Somfleth, K.

Publications and source records attributed to Somfleth, K..

3 recordsLinked to original sources

bioRxiv2025

Identification of host lncRNAs that impact Venezuelan equine encephalitis virus replication

Venezuelan equine encephalitis virus (VEEV) causes encephalitis in humans and equids, and there are no vaccines or therapeutics available for humans. In recent years, non-coding RNAs have emerged as critical regulatory factors affecting different cellular pathways. Specifically, long non-coding RNAs (lncRNAs) have been identified as regulators of antiviral pathways during various viral infections; however, their role in regulating VEEV infection has not been assessed. Here we show differential expression of several lncRNAs in primary mouse target cells infected with a vaccine strain of VEEV (TC-83) but not a pathogenic strain (TrD). Among the differentially expressed genes (DEGs), suppressing lncRNA small nucleolar RNA host gene 15 (Snhg15) resulted in about a 7-fold increase in VEEV TC-83 replication in primary mouse astrocytes. Knockdown of Snhg15 during VEEV TC-83 infection resulted in the suppression of ten genes including Irf1, Junb, Atf3, Relb, Pim1, Hbegf, Ccl5, Ankrd33b, and H2-K2, all of which were also increased during TC-83 infection when the expression of Snhg15 increased in primary mouse astrocytes. Most of these genes are involved in antiviral responses. KEGG pathway analysis confirmed the suppression of both pattern recognition receptor and inflammatory pathways after in Snhg15 knockdown. These data are the first to identify lncRNA responses in encephalitic alphavirus infection and demonstrate important roles for these overlooked RNAs on VEEV infection. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/653438v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@15431eeorg.highwire.dtl.DTLVardef@9a22caorg.highwire.dtl.DTLVardef@1622310org.highwire.dtl.DTLVardef@1ebfd7b_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

CELF2 suppresses endogenous RNA ligands that activate RIG-I-mediated interferon induction

Type I interferons (IFNs) are critical for the control of viral infections, but aberrant IFN expression can result in tissue damage. RIG-I-like receptors (RLRs), such as RIG-I and MDA5, sense viral RNA and signal through the adaptor protein MAVS to induce phosphorylation and nuclear translocation of the transcription factor IRF3, thereby driving IFN production. However, activation of RLRs by endogenous RNA ligands can also induce IFNs, leading to autoinflammation. Identifying factors that suppress endogenous RNA ligands is critical for preventing IFN-induced autoimmunity. In this study, we identify a novel regulator, CELF2, that suppresses endogenous RNAs that otherwise activate the RLR pathway. We uncovered a novel role for the splicing factor CELF2 as a suppressor of immunostimulatory endogenous RNA ligands. Depletion of CELF2 in macrophages led to a spontaneous IFN and IFN-stimulated gene signature, dependent on the RIG-I-MAVS pathway. Furthermore, the transfer of RNA from CELF2-depleted macrophages was sufficient to induce type I IFN expression in naive cells. This RNA was found to be double-stranded as RNase III treatment of RNA derived from CELF2-depleted cells ablated IFN induction in naive cells. Immunoprecipitation of double-stranded RNA from CELF2-depleted macrophages revealed several immunostimulatory RNAs, which contribute to the increased interferon-stimulated gene signature observed in CELF2-depleted macrophages. These data indicate that CELF2 suppresses endogenous RNA ligands, which could otherwise activate RIG-I and induce an IFN signature. Overall, these findings reveal that CELF2 is an important regulator of self-RNA ligands to prevent IFN-induced autoinflammation. One-sentence summaryCELF2 suppresses RIG-I-like receptor ligands that activate interferon.

immunology↗

bioRxiv2023

Cellular RNA interacts with MAVS to promote antiviral signaling

Immune signaling needs to be well-regulated to promote clearance of pathogens, while preventing aberrant inflammation. Interferons (IFNs) and antiviral genes are activated by the detection of viral RNA by RIG-I-like receptors (RLRs). Signal transduction downstream of RLRs proceeds through a multi-protein complex organized around the central adaptor protein MAVS. Recent work has shown that protein complex function can be modulated by RNA molecules providing allosteric regulation or acting as molecular guides or scaffolds. Thus, we hypothesized that RNA plays a role in organizing MAVS signaling platforms. Here, we show that MAVS, through its central intrinsically disordered domain, directly interacts with the 3' untranslated regions of cellular mRNAs. Importantly, elimination of RNA by RNase treatment disrupts the MAVS signalosome, including newly identified regulators of RLR signaling, and inhibits phosphorylation of the transcription factor IRF3. This supports the hypothesis that RNA molecules scaffold proteins in the MAVS signalosome to induce IFNs. Together, this work uncovers a function for cellular RNA in promoting signaling through MAVS and highlights a generalizable principle of RNA regulatory control of cytoplasmic immune signaling complexes.

immunology↗