Dynamic bidirectional regulation between Stk38 and rabies virus M protein coordinates apoptosis progression during
Shujie Wang1, Hao Zhou1, Xi Zhang1
1Key Laboratory of Infectious Diseases and Biosafety, Guizhou Provincial Department of Education, Zunyi Medical University, Zunyi 563000, Guizhou, China; Institute of Life Sciences, Zunyi Medical University, Zunyi 563000, Guizhou, China; School of Preclinical Medicine, Zunyi Medical University, Zunyi 563000, Guizhou, China.
Abstract:
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.
Insights
Rabies virus M protein and host kinase Stk38 regulate each other. Stk38 stabilizes M protein for viral replication, while M protein degrades Stk38, impacting apoptosis. This axis is a potential rabies therapy target.
Area of Science:
- Virology
- Molecular Biology
- Cell Biology
Background:
- Rabies virus (RABV) causes fatal encephalitis, posing a significant zoonotic threat.
- The RABV matrix (M) protein's roles in apoptosis and viral replication are known, but its regulation is unclear.
Purpose of the Study:
- To investigate the regulatory relationship between RABV M protein and host kinase Stk38.
- To elucidate the mechanisms by which this interaction influences viral replication and host cell apoptosis.
Main Methods:
- Protein stability assays to assess M protein and Stk38 degradation.
- Structural analysis to identify key protein domains involved in interaction.
- Mitochondrial localization studies and apoptosis assays.
Main Results:
- Stk38 stabilizes RABV M protein, enhancing viral replication by inhibiting proteasomal degradation.
- Specific domains of Stk38 (1-88, 383-465) are crucial for M protein's mitochondrial localization and pro-apoptotic function.
- RABV M protein (residues 154-202) induces Stk38 degradation during late infection via ubiquitination.
Conclusions:
- A reciprocal regulatory axis exists between RABV M protein and Stk38, involving domain-specific interactions.
- This axis modulates protein stability, coordinating viral replication and apoptosis.
- The Stk38-M protein interaction represents a potential therapeutic target for rabies intervention.
