Dynamic bidirectional regulation between Stk38 and rabies virus M protein coordinates apoptosis progression during neurotropic infection.

Rabies virus (RABV) causes fatal encephalitis in untreated humans, representing a critical global zoonotic threat. Although the viral matrix protein (M) is established as a mediator of mitochondrial apoptosis and enhancer of viral replication, its regulatory mechanisms remain incompletely characterized. This study reveals a reciprocal regulatory axis between RABV M protein and the host kinase Stk38. We demonstrate that Stk38 stabilizes M protein by blocking its ubiquitin-independent proteasomal degradation, thereby potentiating late-stage viral replication. Structural analysis identifies residues 1-88 and 383-465 of Stk38 as non-essential for M binding or stability maintenance, yet crucial for orchestrating M's mitochondrial localization and pro-apoptotic function. Conversely, RABV utilizes residues 154-202 of M protein to induce ubiquitin-dependent degradation of Stk38 during late infection. This mutual regulation establishes domain-specific control mechanisms governing protein stability, facilitating temporal coordination between viral proliferation and apoptotic progression. Our findings elucidate a pathogenic mechanism wherein viral and host factors reciprocally modulate each other's stability through distinct structural domains, positioning the Stk38-M regulatory axis as a promising therapeutic target for rabies intervention.