Piacentini, J. | Search bioRxiv

bioRxiv2026

PQBP1 couples HIV-1 capsid recognition to cGAS recruitment through conformational remodeling

Pattern recognition receptors (PRRs) must selectively engage pathogen-derived signals to potentiate inflammation and antimicrobial responses. Polyglutamine-binding protein 1 (PQBP1) acts upstream of cyclic GMP-AMP synthase (cGAS) during HIV-1 infection through the recognition of viral capsid. However, the mechanism by which capsid binding enables cGAS recruitment remains unclear. As an intrinsically disordered protein, PQBP1 samples an ensemble of conformational states whose distribution depends on ligand engagement. Here we show that capsid engagement shifts this population toward a conformation competent for cGAS binding. Capsid binding at the N-terminus of PQBP1 redistributes conformational sampling within the WW domain and distal polar-rich domain (PRD). Alanine substitutions within these capsid-responsive regions retain capsid binding yet disrupt infection-dependent cGAS recruitment, indicating that capsid binding and cGAS recruitment depend on distinct regions of PQBP1. Together, these findings define a mechanism by which HIV-1 capsid engagement remodels PQBP1 into a cGAS-competent state, coupling capsid recognition to innate immune activation. IMPORTANCEPolyglutamine-binding protein 1 (PQBP1) initiates innate immune detection of HIV-1 by recognizing the incoming viral capsid. We show that capsid engagement reshapes PQBP1 conformational dynamics, and we identify distal regions required for infection-dependent cGAS association. These findings provide a mechanistic framework for how pathogen recognition is coupled to downstream innate immune activation.

molecular biology↗

bioRxiv2026

Developmental delay in attaining adult levels of motor excitability in children and adolescents with Tourette syndrome: a mega-analysis study

Tourette syndrome (TS) is a neurodevelopmental disorder of childhood onset characterised by vocal and motor tics and is associated with cortical-striatal-thalamic-cortical circuit [CSTC] dysfunction. TS often follows a developmental time course in which tics become increasingly more controlled during adolescence. However, many individuals continue to have debilitating tics into adulthood. This indicates that there may be important differences between adults with TS for whom the clinical phenotype is more stable, and children and adolescents with the disorder who may be undergoing developmental neuroplastic changes linked to the reduction of their tics. Previous studies have used transcranial magnetic stimulation (TMS) to investigate changes in cortical motor excitability in individuals with TS, including measurement of resting motor threshold (RMT). However, the findings from these studies have been mixed, have varied between adult and child samples, and have often been based on small sample sizes. Here we report a multi-centre, mega-analytic, study in which RMT data collected from children and adults with TS at multiple research centres was pooled for analysis. Results confirmed that mean RMT was significantly increased in individuals with TS compared to neurotypical controls. However, this result can be explained by the more important findings that: (a) RMT for adults with TS did not differ from that of neurotypical adults; and (b) the rate that RMT decreases with age during childhood and adolescence is reduced in individuals with TS compared to controls. Thus, while neurotypical individuals reach an adult RMT level by ~12-13 years of age, individuals with TS are substantially delayed in doing so, and do not reach an adult RMT level until much later, at ~24 years of age. We conclude therefore that differences in measures of cortical excitability between children and adolescents with TS and chronologically age-matched neurotypical controls may likely reflect a developmental delay in the maturation of functional brain networks in individuals with TS, which may normalise with age.

neuroscience↗