Biology subjects

Balci, A.

Publications and source records attributed to Balci, A..

3 recordsLinked to original sources

bioRxiv2025

ZNFX1 uses two-component ubiquitin circuitry to quarantine viral RNA

The detection of viral RNA inside cells triggers a diverse range of antiviral responses, including global translation inhibition, interferon secretion and RNA sequestration. Mutations in the gene ZNFX1 cause severe paediatric immunodeficiencies, including chronic viral infection and autoinflammation. Here, we show that ZNFX1 is an RNA helicase with cryptic and unusual bifurcating E3 ubiquitin ligase activity. Nucleotide-dependent RNA binding stimulates ZNFX1 to generate complex ubiquitin chains via a two-component ubiquitin circuit wired in parallel, with ubiquitin flux occurring via either of two competing paths. One route produces K63-linked polyubiquitin that drives ZNFX1 aggregation and RNA entrapment; the other route produces K48-linked polyubiquitin that drives ZNFX1 turnover. RNA entrapment restricts RNA virus replication, and is reversible by deubiquitination. Patient ZNFX1 variants are defective for viral restriction, linking RNA entrapment to antiviral immunity in vivo.

biochemistry↗

bioRxiv2025

Alternative splicing broadens antiviral diversity at the human OAS2 locus

Interferons (IFN) are cytokines that regulate the expression of hundreds of genes during viral infections to generate a broadly antiviral environment in the stimulated cell. Antiviral breadth is provided by the concurrent expression of many individual IFN-stimulated genes (ISG), each encoding a protein with often exquisite antiviral specificity. Here, we show that mechanistic plasticity at a single genetic locus is a novel mechanism to diversify the antiviral profile of human cells. Through alternative splicing, the OAS2 gene encodes two antiviral molecules with distinct target specificities. The shorter OAS2 p69 isoform blocks the replication of seasonal human coronavirus OC43 (HCoV-OC43), while the longer p71 isoform restricts the replication of picornavirus Cardiovirus A (EMCV). The restriction profile is determined by the variable length OAS2 C-terminal tail. Remarkably, the antiviral mechanisms underlying these distinct antiviral profiles are either RNase L dependent or independent, suggesting that splicing divides classic restriction versus virus sensing systems across two distinct OAS2 polypeptides. Together, our data reveal that the human OAS2 locus uses alternative splicing and mechanistic plasticity to diversify antiviral profiles.

microbiology↗

bioRxiv2019

Salmonella Typhi survives in human macrophages by neutralizing the RAB32/BLOC-3 host-defence pathway

Macrophages provide a first line of defence against microorganisms, and while some mechanisms to kill pathogens such as the oxidative burst are well described, others are still undefined or unknown. Here we report that the Rab32 GTPase and its guanine nucleotide exchange factor BLOC-3 are central components of a trafficking pathway that controls both bacterial and fungal intracellular pathogens. This broad host-defence mechanism is active in both human and murine macrophages and is independent of well known antimicrobial mechanisms such as the NADPH-dependent oxidative burst, production of nitric oxide and antimicrobial peptides. To survive in human macrophages, Salmonella Typhi actively counteracts the Rab32/BLOC-3 pathway through its Salmonella pathogenicity island-1-encoded type III secretion system. These findings demonstrate that the Rab32/BLOC-3 pathway is a novel and universal host-defence pathway and protects mammalian species from a wide range of intracellular pathogens.

microbiology↗