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 cytotoxi c lymphocyte granule protease that plays a critical role in mediating cytot oxicity. In these studies, we demonstrate that the adenovirus assembly prot ein L4-100K (100K) is a GrB substrate that prevents cytotoxic lymphocyte gr anule-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 tha t 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 fu nction against that protease.