As a major pathway of reversible protein modification in eukaryotes cells, leading to their degradation, affecting their subcellular localization, or activity, the Ubiquitin Proteasome System (UPS) is a prime target of viruses. Recent evidence indicates that the UPS contributes to the infectious cycle of influenza viruses, but the nature of influenza-UPS interplay is still elusive. We are currently studying the interplay of the viral polymerase with UPS. To that end, we constructed and fully characterized a library consisting of 582 UPS human factors, covering about half of the human UPS pathway. This UPS library has been used to screen for interactions with the viral polymerase sub-unit PB2 of 6 strains of influenza virus A of various virulence in humans using the split-luciferase complementation assay. UPS targets of the PB2 protein are currently being analyzed for their role in viral cycle. Particular focus is placed on several De-ubiquitinating enzymes (DUBs), which have emerged as partners of the viral polymerase. For these DUBs, the interaction with other viral proteins and potential impact on viral cycle is studied as well.