Molecular analysis of the interaction between ubiquitin-specific protease 7 and large T antigen of Merkel cell polyomavirus

Merkel cell polyomavirus (MCPyV) is the primary causative agent of Merkel cell carcinoma, a rare but highly aggressive neuroendocrine skin cancer. Large T antigen (LT), one of two oncoproteins encoded by MCPyV, sustains the proliferation of MCPyV-infected tumor cells. LT contains multiple protein-binding motifs that mediate interactions with diverse host proteins essential for its function. Among these, ubiquitin-specific protease 7 (Usp7), a deubiquitinase that regulates the stability of multiple substrates, including p53, is a recently identified LT-interacting protein. In the present study, we characterized the intermolecular interaction between Usp7 and MCPyV LT using biochemical analyses and AlphaFold-based structural modeling. Our results demonstrate that MCPyV LT directly interacts with the TRAF domain of Usp7 via a unique binding motif that is distinct from the canonical sequence. Moreover, MCPyV LT attenuates the p53-deubiquitinating activity of Usp7, providing insights into the molecular function of this viral oncoprotein.