Contagious bovine pleuropneumonia (CBPP), caused by Mycoplasma mycoides subsp. mycoides (Mmm), is a devastating cattle disease with high morbidity and mortality. Although mass vaccination or stamping-out strategy has controlled CBPP in many countries, it remains a major threat to cattle productivity in sub-Saharan Africa. An attenuated vaccine derived from serial passages of the virulent Ben-1 strain has eradicated CBPP in China, but the underlying immunoprotective mechanisms are unclear. While interferon-inducible GTPases are known to play a crucial role in host defense, IRG-47, an interferon-gamma (IFN-γ)-inducible GTPase, was previously thought to have limited anti-infective activity. Here, we demonstrate that IRG-47 is critical for defending against Mmm and is specifically upregulated by the Ben vaccine strain. Screening potential protective proteins in this vaccine strain revealed that Ben_0691 is a key factor responsible for boosting IRG-47 to combat Mmm infection. Mechanistically, Ben_0691 binds directly to the host cell ATP synthase subunit alpha (ATP5A1) and stabilizes ATP5A1 by reducing its autophagic-degradation. This stabilization promotes IRG-47 expression, which disrupts Mmm's early cell-associativity and provides resistance to Mmm infection. Notably, Ben_0691 N-terminal amino acids 66-72 are required for its interaction with ATP5A1, the induction of IRG-47 and anti-Mmm action. The AMPK-mTOR-IFN-γ pathway is further characterized as an essential signaling for ATP5A1 to facilitate IRG-47 expression. Together, our study reveals a previously unrecognized role of IRG-47 in defending against Mmm infection, and the protective mechanism of Ben_0691 as an IRG-47 activator. These findings provide new insights into vaccine-based protection strategies and may inform future CBPP control strategies.