Biology subjects

Storer, F.

Publications and source records attributed to Storer, F..

3 recordsLinked to original sources

bioRxiv2026

Phosphoinositide turnover through PLCγ regulates Draper-dependent engulfment in glia

Glial engulfment of degenerating neuronal material is essential for nervous system development, maintenance and repair. Genome-wide association studies have identified protective variants in the phosphoinositide-metabolising enzyme PLCG2 that modify Alzheimers disease risk, but how PLCG2-dependent phosphoinositide signalling regulates glial engulfment remains unclear. Using Drosophila, we investigated the role of small wing (sl), the fly orthologue of human PLCG2, in glial responses to axonal injury and amyloid pathology. Glial knockdown of sl altered immune-associated transcriptional pathways and significantly delayed clearance of degenerating olfactory receptor neuron axons following axotomy. Loss of sl disrupted injury-induced phosphoinositide remodelling, resulting in elevated basal PIP2 levels and impaired post-injury accumulation of PIP3. Similar defects were observed following knockdown of the engulfment receptor Draper, placing phosphoinositide turnover downstream of Draper signalling. Simultaneous Pten knockdown restored phosphoinositide signalling and rescued delayed neuronal clearance in sl-deficient glia. Loss of sl also prevented injury-induced Draper upregulation and disrupted glial calcium signalling responses to axonal injury. In a model of A{beta}42 accumulation, sl knockdown altered brain PIP2/PIP3 balance and improved survival independently of amyloid burden. Together, these findings identify PLC{gamma}-dependent phosphoinositide turnover as a conserved regulator of Draper-mediated glial engulfment and provide mechanistic insight into how PLCG2 influences glial function and neurodegenerative disease risk. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/729572v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@5beb6org.highwire.dtl.DTLVardef@12bc7c5org.highwire.dtl.DTLVardef@1486ba0org.highwire.dtl.DTLVardef@1921395_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Sex-lethal is recruited to chromatin to promote neuronal tRNA synthesis in males through RNA Polymerase III regulation

The RNA-binding protein Sex-lethal (Sxl) is classically known as a master regulator of sex determination and mRNA splicing in Drosophila melanogaster. However, this role is not conserved across species, and functions beyond this canonical pathway remain poorly understood. In this study, we uncover a splicing-independent role for Sxl at the chromatin level in the Drosophila brain. Using Targeted DamID (TaDa) profiling in neurons, we identify widespread recruitment of Sxl to promoter regions, independent of sex or RNA binding activity. Notably, Sxl chromatin occupancy exhibits near-complete overlap with Polr3E (RPC37), an RNA Polymerase III subunit, with Sxl binding abolished upon Polr3E knockdown. Depletion of Sxl in mature male neurons induces widespread transcriptional changes, particularly in metabolic genes, and improves negative geotaxis during ageing, phenotypes that closely mirror Polr3E knockdown. Conversely, overexpression of the brain-specific SxlRAC transcript leads to enhanced tRNA synthesis and upregulated metabolic gene expression. Together, these findings reveal a previously unrecognised role for Sxl in regulating Pol III activity via Polr3E, regulating tRNA synthesis and supporting neuronal metabolism. Given the emerging tie between Pol III regulation and neuronal ageing, our study highlights Sxl as a novel modulator of neuronal homeostasis.

molecular biology↗

bioRxiv2024

OST component RPN1 is a novel regulator of IRE1 RNase activity that interacts with multiple distinct IRE1 and PERK complexes

The unfolded protein response (UPR) is an essential cell signalling system that regulates ER protein homeostasis. IRE1 and PERK are receptor proteins that propagate the UPR signal from the ER to the cytosol. Both receptors are suggested to interact with various proteins from different biological pathways, although the scale and scope of such interactions are unclear. Previous reconstitution experiments have utilized purified isolated domains of IRE1 and PERK to understand mechanism. Here, we affinity purify full length IRE1 and PERK from mammalian cells and characterise the complexes they form by biochemical techniques and assess RNase function in vivo. We identify RPN1 as a novel interacting protein present in complexes with IRE1 and PERK. In the Drosophila eye, RNAi knockdown of RPN1 results in loss of IRE1 RNase activity. This work provides a basis for understanding of protein interaction networks for IRE1 and PERK and identifies OST subunit RPN1 as a novel regulator of IRE1 RNase activity.

biochemistry↗