Adenovirus L4-100K assembly protein is a Granzyme B substrate that potently inhibits Granzyme B-mediated cell death

Cytotoxic lymphocytes kill virus-infected target cells and play a critical role in host recovery from viral infections. Granzyme B (GrB) is a cytotoxic lymphocyte granule protease that plays a critical role in mediating cytotoxicity. In these studies, we demonstrate that the adenovirus assembly protein L4-100K (100K) is a GrB substrate that prevents cytotoxic lymphocyte granule-induced apoptosis in infected target cells by potently inhibiting GrB. This inhibition is absolutely dependent on Asp-48 in 100K, found within a classic GrB consensus motif. 100K is the first viral protein described that exclusively targets the GrB pathway. It represents a novel class of viral protease inhibitor, in which an essential, multifunctional viral protein, which is vulnerable to specific proteolysis by GrB, expresses inhibitory function against that protease.