Biology subjects

Towler, B.

Publications and source records attributed to Towler, B..

3 recordsLinked to original sources

bioRxiv2026

XRN1 couples RNA granule remodelling to global mRNA decay triggered by the activity of a viral endoribonuclease

Cytoplasmic mRNA turnover is a fundamental determinant of gene expression, yet the spatial organisation of RNA decay remains unresolved. Although decay factors are enriched in processing (P)-bodies, whether these condensates actively mediate mRNA degradation or serve primarily as storage compartments remains controversial. Here, we exploit the alphaherpesvirus endoribonuclease, virion host shutoff (vhs), to synchronously trigger rapid, global cytoplasmic mRNA accompanied by nuclear relocalisation of the poly(A)-binding protein PABPC1. Expression of vhs caused the dispersal of P-bodies, but when the 5' to 3' exonuclease XRN1 was depleted, PABPC1 remained in the cytoplasm, and P-bodies stayed intact, associating with previously undetected G3BP1-dependent RNA granules. Similarly, catalytically inactive vhs failed to disperse P-bodies but instead induced RNA granules that also contained vhs itself and recruited decay factors in an XRN1-dependent manner. Translational shutoff by this endoribonuclease did not require RNA cleavage, G3BP1 condensation or XRN1 activity supporting a sequential model in which translational arrest precedes endonucleolytic cleavage, promoting transient RNA granules that engage P-bodies and XRN1-dependent machinery for rapid mRNA degradation within the granules, thereby precluding the biogenesis of deleterious RNA condensates.

cell biology↗

bioRxiv2026

Nonlinear sensory integration drives configural olfactory representations

Natural environments are composed of complex stimulus mixtures that can be perceived either as combinations of known components (elemental coding) or acquire entirely new qualities (configural coding). While configural representation is traditionally viewed as a high-order emergent property of cortical processing, the underlying circuit mechanisms remain elusive. Employing C. elegans, we demonstrate that the neural foundations of configural representation can be established already at the sensory periphery. For most mixtures, single neuron responses arise through linear integration of the individual components. However, for a subset of mixtures, a small number of sensory neurons exhibit strong nonlinear integration, including NAND/XOR-like logic-gates computations. These nonlinear integrations collectively generate configural population codes. We present a novel quantitative predictor of configural representation and demonstrate that mixtures classified as configural induce emergent synergistic attraction and may lead to violations of rational choice behavior. Together, our findings identify single-neuron nonlinearities as a mechanistic link between sensory circuit dynamics and complex perceptual and decision-making outcomes.

neuroscience↗

bioRxiv2025

TOE1 influences canonical Wnt signalling in myeloid leukaemia cells through LEF-1 modulation and regulates the proliferation of haematopoietic cells through PAK2.

Acute myeloid leukaemia (AML) is an aggressive haematological malignancy characterised by the clonal proliferation of myeloid progenitor cells in the bone marrow and peripheral blood. Dysregulation of the Wnt/{beta}-catenin pathway has been implicated in the establishment and maintenance of leukaemic stem cells in AML, where higher expression of {beta}-catenin promotes clonogenic capacity, drug resistance and inferior survival. The finding that low levels of Wnt signalling are necessary to maintain normal haematopoiesis makes {beta}-catenin an attractive therapeutic target; however, drug design has been hampered by a poor understanding of its molecular interactions in leukaemia cells. To address this, we previously characterised the {beta}-catenin interactome in myeloid cells and identified a plethora of novel interacting proteins. One such interactor was Target of EGR1 (TOE1), a member of the Asp-Glu-Asp-Asp (DEDD) family of deadenylases with previously uncharacterised function in haematopoietic cells. The {beta}-catenin:TOE1 interaction was detected in the nuclear and cytosolic compartments of myeloid cell lines and primary AML samples, and {beta}-catenin depletion was found to promote the cytosolic accumulation of TOE1. Furthermore, TOE1 levels were found to be overexpressed in primary AML blasts versus normal cord-blood derived CD34+ haematopoietic stem and progenitor cells (HSPCs), suggesting that TOE1 levels may be dysregulated in leukaemia. TOE1 depletion abrogated Wnt signalling capacity (TCF/LEF activity), potentially via reduced stability/translatability of the Wnt transcription factor lymphoid enhancing factor 1 (LEF-1). TOE1 depletion further suppressed the proliferation and survival of myeloid leukaemia cell lines (HEL and OCI-AML2) and primary human CD34+ HSPC; however, this could not be fully explained through LEF-1 alone, since OCI-AML2 do not express LEF-1. Using tandem mass tag (TMT)-labelling coupled to mass spectrometry analysis in TOE1 deficient HEL and OCI-AML2 cells, we identified and validated p21 (RAC1) activated kinase 2 (PAK2) as a downregulated target that could reduce the proliferation (but not survival) of AML cell lines. Interestingly, ectopic expression of PAK2 was able to partially rescue the proliferation defect in TOE1 depleted myeloid cell lines and primary human CD34+ HSPC. In summary, these data reveal TOE1 as novel interacting partner for {beta}-catenin in haematological cells capable of modulating Wnt signalling output via LEF-1, and as a novel mediator of growth and survival in human HSPC and AML cells partly through PAK2 regulation.

cancer biology↗