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) functions upstream of cyclic GMP-AMP synthase (cGAS) during HIV-1 infection primarily through the recognition of viral capsid. However, the mechanism by which capsid binding enables cGAS recruitment remains unclear. As an intrinsically disordered protein, PQBP1 likely samples an ensemble of conformational states. Here we show that capsid engagement shifts this population toward a conformation competent for cGAS binding. Capsid binding at the N-terminal pore-binding region redistributes conformational sampling within the WW domain. Distal regions of the polar-rich domain (PRD) also become shielded from solvent, a signature of long-range conformational effects after binding. Alanine substitutions in these capsid-responsive regions retain capsid binding yet disrupt infection-dependent cGAS recruitment. This indicates that capsid binding and cGAS recruitment are separable PQBP1 functions. Together, these findings define a mechanism in which N-terminal capsid engagement is transduced through the WW domain to the PRD, positioning PQBP1 for cGAS recruitment during the innate sensing of HIV-1 capsid.