アテローム性動脈硬化症の病態生理におけるマクロファージの役割

Autophagosome formation is catalyzed by multiple branches of Atg protein machineries, calling for the existence of a master regulator to coordinate their distinct activities. A prime candidate of such a regulator is Atg8. This protein has a well-established role in controlling phagophore expansion. But the signaling mechanism has been unclear. Our recent work demonstrates that Atg8 recruits activated Atg1 to the phagophore, together forming such a master switch. Our data indicate that different branches of Atg proteins localize to spatially separated zones. The physical distances among the zones, at times exceeding 250 nm, would limit signal transduction efficiency if a signaling molecule were exclusively localized to a single zone. By covering the phagophore surface, Atg8 maintains physical proximity to different Atg machineries, and transmits a permissive signal by recruiting activated Atg1. Compromising Atg8-mediated Atg1 recruitment leads to confinement of Atg1 to the initiation protein condensate and failure of phagophore expansion. Conversely, the Atg8-Atg1 switch can be manually augmented to substantially increase autophagosome size and autophagic flux. Our work thus reveals a critical regulatory circuit of macroautophagy/autophagy that is built on the spatial organization of Atg protein machineries.