Autophagy is a highly regulated self-degradative mechanism required at a basal level for intracellular clearance and recycling of cytoplasmic contents. Upon intracellular pathogen invasion, autophagy can be induced as an innate immune mechanism to control infection. Nevertheless, pathogens have developed strategies to avoid or hijack autophagy for their own benefit. The molecular pathways inducing autophagy in response to infection remain poorly documented. We report here that the engagement of CD46, a ubiquitous human surface receptor able to bind several different pathogens, is sufficient to induce autophagy. CD46-Cyt-1, one of the two C-terminal splice variants of CD46, is linked to the autophagosome formation complex VPS34/Beclin1 via its interaction with the scaffold protein GOPC. Measles virus and group A Streptococcus, two CD46-binding pathogens, induce autophagy through a CD46-Cyt-1/GOPC pathway. Thus, upon microorganism recognition, a cell surface pathogen receptor can directly trigger autophagy, a critical step to control infection.