ASFV p54 manipulates the secretory carrier membrane protein 3-dependent apoptotic bodies pathway to enhance cell-cell transmission

The African swine fever virus (ASFV) is a significant threat to the global swine industry, with no effective vaccine available. ASFV subverts cellular processes, including programmed cell death mechanisms, to enhance its transmission and pathogenicity. Here, we show that the ASFV p54 manipulates the secretory carrier membrane protein 3 (SCAMP3)-dependent apoptotic bodies (ApoBDs) pathway to facilitate cell-cell transmission, thereby enhancing viral replication. We demonstrate that p54 interacts with SCAMP3 via its carboxyl-terminal 150-184 amino acids, which is critical for the formation of ApoBDs induced by ASFV. Deletion of this motif in ASFV significantly impairs the release of virions, leading to intracellular viral accumulation and triggering ferroptosis instead of apoptosis. This shift in cell death mechanism significantly reduces virulence and provides protection against lethal challenges with wild-type ASFV. Our findings reveal a mechanism of ASFV-induced cell death and intercellular transmission, providing a theoretical foundation for developing future vaccine strategies against ASFV.