Biology subjects

Staes, K.

Publications and source records attributed to Staes, K..

3 recordsLinked to original sources

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↗

bioRxiv2025

Canonical Wnt induction by OTULIN prevents keratinocyte death and skin inflammation

Loss-of-function mutations in the human OTULIN gene, encoding a deubiquitinase with exclusive specificity for linear ubiquitin chains, cause a severe multi-organ autoinflammatory condition involving the skin1,2. Mice lacking OTULIN selectively in keratinocytes develop inflamed skin lesions that progress into squamous tumours, a phenotype driven by excessive TNF-induced cell death3,4. Previous studies suggested a role for OTULIN in mediating Wnt signalling during development5, but the physiological relevance of this association is unknown. Here, we show that OTULIN promotes Wnt signalling in keratinocytes by regulating the linear ubiquitination status of {beta}-catenin. Stabilisation of {beta}-catenin in OTULIN-deficient keratinocytes prevents progressive skin inflammation in prophylactic and therapeutic settings by blocking keratinocyte death. We demonstrate that linearly ubiquitinated {beta}-catenin accumulates in OTULIN-deficient keratinocytes, promoting its ubiquitination with K48 chains and subsequent proteasomal degradation. Reduced Wnt signalling in OTULIN-deficient keratinocytes leads to degradation of TCF3, an essential survival factor for keratinocytes6. Collectively, our data identify OTULINs linear deubiquitination activity as a key regulator of epithelial cell viability, not only by preventing cell death downstream of TNF, but also by promoting canonical Wnt signalling.

cell biology↗

bioRxiv2020

ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation.

Loss-of-function of ADAR1 causes the severe autoinflammatory disease Aicardi-Goutieres Syndrome (AGS). ADAR1 converts adenosines into inosines within double-stranded (ds) RNA. This process called A-to-I editing masks self-dsRNA from detection by the antiviral dsRNA sensor MDA5. ADAR1 binds to dsRNA in both the canonical A-form and in the poorly defined Z-conformation (Z-RNA). Mutations in the Z-RNA binding Z-domain of ADAR1 are common in AGS patients. How loss of ADAR1/Z-RNA interaction contributes to disease development is unknown. Using ADAR1 Z-domain mutant human cells and knock-in mice, we demonstrate that abrogated binding of ADAR1 to Z-RNA leads to reduced A-to-I editing of dsRNA structures formed by pairing of inversely oriented SINEs. As a result, ADAR1 Z-domain mutant human cells and transgenic mice develop a spontaneous MDA5-dependent immune response. This shows that the interaction between ADAR1 and Z-RNA restricts sensing of self-dsRNA and prevents AGS development.

immunology↗