title: Cathepsins are involved in virus-induced cell death in ICP4 and Us3 deletion mutant herpes simplex virus type 1-infected monocytic cells.
abstract: We have studied cell death and its mechanisms in herpes simplex virus type 1 (HSV-1)-infected monocytic cells. The HSV-1 ICP4 and Us3 deletion mutant, d120 caused both apoptosis and necroptosis in d120-infected monocytic cells. At a late time point of infection the number of apoptotic cells was increased significantly in d120-infected cells when compared with uninfected or parental HSV-1 (KOS)-infected cells. Necroptosis inhibitor treatment increased the number of viable cells among the d120-infected cells, indicating that cell death in d120-infected cells was, in part, because of necroptosis. Moreover, lysosomal membrane permeabilization and cathepsin B and H activities were increased significantly in d120-infected cells. Inhibition of cathepsin B and S activities with specific cathepsin inhibitors led to increased cell viability, and inhibition of cathepsin L activity resulted in a decreased number of apoptotic cells. This indicates that cathepsins B, L and S may act as cell-death mediators in d120-infected monocytic cells. In addition, caspase 3 activity was increased significantly in d120-infected cells. However, the caspase 3 inhibitor treatment did not decrease the number of apoptotic cells. In contrast, inhibition of cathepsin L activity by cathepsin L-specific inhibitor clearly decreased caspase 3 activity and the number of apoptotic cells in d120-infected cells. This might suggest that, in d120-infected monocytic cells, cathepsin L activates caspase 3 and thus mediates d120-induced apoptosis. Taken together, these findings suggest that d120-induced cell death is both apoptotic and necroptotic.
authors.affiliation: Department of Virology, University of Turku, Kiinamyllynkatu 13, FI-20520 Turku, Finland. piritta.peri@utu.fi
authors.forename: Piritta
authors.initials: P
authors.lastname: Peri
authors.forename: Kristiina
authors.initials: K
authors.lastname: Nuutila
authors.forename: Tytti
authors.initials: T
authors.lastname: Vuorinen
authors.forename: Pekka
authors.initials: P
authors.lastname: Saukko
authors.forename: Veijo
authors.initials: V
authors.lastname: Hukkanen
mesh_terms: D053148:Caspase 3 / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D017353:Gene Deletion; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000472:pathogenicity*; D006801:Humans; D017874:Immediate-Early Proteins / Q000172:deficiency*; D008247:Lysosomes / Q000502:physiology; D009000:Monocytes / Q000821:virology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D014764:Viral Proteins
chemical_list: D017874:Immediate-Early Proteins; D014764:Viral Proteins; C048925:herpes simplex virus, type 1 protein ICP4; D017346:Protein Serine-Threonine Kinases; C095207:US3 protein, Human herpesvirus 1; D002403:Cathepsins; D053148:Caspase 3