Yang et al. identify USP39 as a deubiquitinase hijacked by H5 AIV. USP39 catalytically deubiquitinates PB2 to prevent its degradation and maintain polymerase activity. Meanwhile, it promotes PB2-PB1 association for RNP assembly. The dual-function mechanism facilitates viral replication, enhances pathogenicity, and represents a promising anti-H5 therapeutic target.