**1. Introduction**

Ubiquitination is a reversible post-translational modification (PTM) that regulates protein functions in almost every aspect of a cell's life. Conjugation of a 76-amino acid small protein, ubiquitin (Ub), to a target protein changes the stability, quantity and activity of that target. Ubiquitination was first discovered as a type of histone H2A modification about 43 years ago [1,2]. Later, it became clear that protein ubiquitination triggers selective degradation of the target and plays essential roles in many cellular processes [3]. After decades of e fforts to delineate the regulation of ubiquitin enzymes and the network of ubiquitin linkage, now we know that the complex ubiquitin code is a major form of cellular communication that conveys distinct signals in cell pathways such as receptor signaling transport, DNA damage response, cell cycle progression, and stress responses (for recent reviews, see references [4–6]).

Viruses are obligate parasites that closely interact with the host to subjugate many cellular machineries to achieve viral replication. Naturally, they have evolved to manipulate and take advantage of the ubiquitin system so as to redirect the cellular pathways in their own favor. Host cells also adopt special code of ubiquitination to mount immune responses against viral infection. It is fascinating to witness the unveiling of ubiquitin regulation in cell anti-viral defenses as well as viral counteractions in recent years. In this review we will focus on the current advances of understanding the specificity of ubiquitination in the constant battles between the virus and its host. Through delineating the complex ubiquitin code on both the virus and host factors, we hope to understand the significance of ubiquitination specificity in virus-host interaction and to search for potential targets useful for prophylactic and therapeutic treatment of viral diseases.
