Biology subjects

Nemegeer, J.

Publications and source records attributed to Nemegeer, J..

3 recordsLinked to original sources

bioRxiv2025

Nodamuravirus protein B2 boosts self-amplifying mRNA efficacy by overcoming innate immune barriers.

Self-amplifying RNA (sa-RNA) technology is a promising strategy for vaccine design, as its intracellular replication boosts transgene expression and provides self-adjuvanticity. However, sa-RNA efficiency is limited by innate immune responses triggered by the presence of intracellular double-stranded RNA (dsRNA). In vertebrates, differentiated cells mainly use type I interferon (IFN) system for protection against viruses, while stem cells rely on IFN-independent mechanisms such as antiviral RNA interference (RNAi). Here, we found that the efficiency of sa-RNAs based on chikungunya virus (CHIKV) or Venezuelan equine encephalitis virus (VEEV) genomes is enhanced when co-expressed in cis with the Nodamura virus (NoV) B2 protein, a viral suppressor of RNAi. In stem cells, NoV B2 prevents Dicer-mediated processing of dsRNA, while in somatic cells, it blocks the translation shutdown caused by protein kinase R (PKR), a key effector of the IFN system. Notably, NoV B2 does not interfere with IFN induction and signalling, preserving sa-RNAs self-adjuvant properties. Mechanistically, NoV B2 sequesters replication-derived dsRNA at the cell periphery, offering a novel strategy to boost sa-RNA efficiency without compromising its immune stimulatory properties. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/661928v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@4412aforg.highwire.dtl.DTLVardef@126d089org.highwire.dtl.DTLVardef@144dd38org.highwire.dtl.DTLVardef@179bac_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Zα domain-dependent ZBP1 condensate formation induces an amyloidal necroptotic signalling complex

ZBP1 restricts viral replication by inducing host cell death. ZBP1 recognises Z-RNA or Z-DNA, left-handed double-stranded RNA or DNA structures that accumulate after virus infection. How the interaction between Z-RNA/DNA and ZBP1 governs its activation and how this mediates downstream signalling remains unclear. Using herpes simplex virus 1 (HSV-1) as an activator of human ZBP1 we find that binding of the N-terminal Z domains of ZBP1 to Z-RNA induces ZBP1 condensate formation. This then mediates oligomerisation of the RIP homotypic interaction motifs (RHIMs) of ZBP1 establishing an amyloidal signalling complex with RIPK1 and RIPK3 that induces necroptotic cell death. We find that the kinase activity of RIPK1 is essential for RIPK1 and RIPK3 oligomerisation downstream of human ZBP1. Finally, the HSV-1-encoded RHIM-containing protein ICP6, does not interfere with Z domain-mediated ZBP1 condensate formation, but instead prevents downstream RIPK1 and RIPK3 oligomerisation thereby inhibiting necroptosis and promoting viral growth. Together, this shows that ZBP1 condensate formation restricts HSV-1 infection by promoting host cell necroptosis.

immunology↗

bioRxiv2020

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Aberrant detection of endogenous nucleic acids by the immune system can cause inflammatory disease. The scaffold function of the signalling kinase RIPK1 limits spontaneous activation of the nucleic acid sensor ZBP1. Consequently, loss of RIPK1 in keratinocytes induces ZBP1-dependent necroptosis and skin inflammation. Whether nucleic acid sensing is required to activate ZBP1 in RIPK1 deficient conditions and which immune pathways are associated with skin disease remained open questions. Using knock-in mice with disrupted ZBP1 nucleic acid binding activity, we report that sensing of endogenous nucleic acids by ZBP1 is critical in driving skin pathology characterised by antiviral and IL-17 immune responses. Inducing ZBP1 expression by interferons triggers necroptosis in RIPK1-deficient keratinocytes and epidermis-specific deletion of MLKL prevents disease, demonstrating that cell-intrinsic events cause inflammation. These findings indicate that dysregulated sensing of endogenous nucleic acid by ZBP1 can drive inflammation and may contribute to the pathogenesis of IL-17-driven inflammatory skin conditions such as psoriasis. SummaryDevos, Tanghe et al. find that the recognition of endogenous nucleic acids by the nucleic acid sensor ZBP1 causes necroptosis of RIPK1-deficient keratinocytes. This process drives the development of an inflammatory skin disease characterised by an IL-17 immune response.

immunology↗