Calcium influx is a universal early signal triggering membrane repair pathways, yet how Ca ²⁺ sensors coordinate the balance between ESCRT-mediated sealing and autophagy-based responses at damaged endolysosomes and pathogen-containing vacuoles remains unclear. Here we use the Dictyostelium discoideum-Mycobacterium marinum infection model, a surrogate to study intracellular pathogenesis of Mycobacterium tuberculosis , combined with genetic, imaging, and proteomic analyses to identify the penta-EF-hand protein PefA, an ALG-2-like Ca ²⁺ sensor, as a Ca ²⁺ -responsive regulator that orchestrates recruitment of the E3 ubiquitin ligase TrafE, ESCRT components, and the autophagy machinery to damaged membranes. PefA is transcriptionally upregulated and accumulates at the mycobacterial vacuole, promoting timely repair that preserves vacuolar integrity and supports bacterial replication. Loss of PefA impairs ESCRT and autophagy engagement, leading to premature bacterial escape to the cytosol and altered infection outcomes. These findings uncover a conserved Ca ²⁺ -dependent mechanism linking membrane damage sensing to coordinated repair pathways and shapes host-pathogen interactions, with direct relevance to tuberculosis pathogenesis and host resilience to infection.