Once rabies virus (RABV) gains access to the central nervous system, infection almost inevitably results in fatal outcomes, and our incomplete understanding of viral pathogenesis remains a major barrier to effective therapeutic intervention. Here, we identify CAMKV as an interferon-stimulated gene (ISG) that drives the macroautophagic/autophagic degradation of RABV phosphoprotein (P), thereby potently suppressing viral replication in vitro. Notably, in vivo overexpression of CAMKV significantly delays disease progression in mice challenged with a street strain of RABV. Mechanistically, CAMKV interacts with both RABV P and SQSTM1, promoting SQSTM1-mediated selective autophagic clearance of P and thereby restricting RABV transcription and replication. Collectively, our findings establish CAMKV as a critical host antiviral effector that functions through selective autophagy, highlighting CAMKV as a promising molecular target for the development of novel therapeutics against lethal RABV infection. Abbreviation: 3-MA: 3-methyladenine; ABLV: Australian bat lyssavirus; ATG: autophagy related; AKT: AKT serine/threonine kinase; Baf-A1: bafilomycin A1; CAMKV: CaM kinase like vesicle associated; CAMK2: calcium/calmodulin dependent protein kinase II; co-IP: co-immunoprecipitation; CQ: chloroquine; DUVV: Duvenhage virus; DMSO: dimethyl sulfoxide; EBLV-1: European bat lyssavirus 1; ISG: interferon stimulated gene; LAMP1: lysosome associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; Mdivi-1: mitochondrial division inhibitor-1; MLD₅₀: 50% mouse lethal dose; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; qPCR: quantitative real-time polymerase chain reaction; RABV: rabies virus; SQSTM1/p62: sequestosome 1; WT: wild type.

Keywords: Autophagy; CAMKV; phosphoprotein; rabies virus; virus replication.