title: Role of cathepsin B in dengue virus-mediated apoptosis.
abstract: Dengue virus (DENV) infection is one of the most important mosquito-borne viral diseases, which is endemic in the tropical and sub-tropical regions. Patients with dengue hemorrhagic fever (DHF) generally present hemorrhagic tendencies, plasma leakage, thrombocytopenia, and hemoconcentration. Hepatic dysfunction is also a crucial feature of DENV infection. Hepatic biopsy specimens obtained from fatal cases of DENV infection show cellular apoptosis, which apparently relate to the pathogenesis. Cathepsins, which are cysteine proteases inside the lysosome, were previously reported to be up-regulated in patients with DHF. However, their functions during DENV infection have not been thoroughly investigated. We show for the first time that DENV induces lysosomal membrane permeabilization. The resulting cytosolic cathepsin B and S contributed to apoptosis via caspase activation. The activity of caspase 3 was significantly reduced in DENV-infected HepG2 cells treatedwith cathepsin B or S inhibitors. Treatment with cathepsin B inhibitor also reduced the activity of caspase 9, suggesting that cathepsin B activates both caspase-9 and caspase-3. Reduced cathepsin B expression, effected by RNA interference, mimicked pharmacological inhibition of the enzyme and confirmed the contribution of cathepsin B to apoptotic events induced by DENV in HepG2 cells.
authors.affiliation: Division of Molecular Medicine, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Atthapan
authors.initials: A
authors.lastname: Morchang
authors.forename: Jutatip
authors.initials: J
authors.lastname: Panaampon
authors.forename: Aroonroong
authors.initials: A
authors.lastname: Suttitheptumrong
authors.forename: Umpa
authors.initials: U
authors.lastname: Yasamut
authors.forename: Sansanee
authors.initials: S
authors.lastname: Noisakran
authors.forename: Pa-thai
authors.initials: PT
authors.lastname: Yenchitsomanus
authors.forename: Thawornchai
authors.initials: T
authors.lastname: Limjindaporn
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism* / Q000821:virology*; D002463:Cell Membrane Permeability / Q000502:physiology*; D003716:Dengue Virus / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans
chemical_list: D053148:Caspase 3; D053453:Caspase 9; C533912:CTSB protein, human; D002401:Cathepsin B
keywords: Apoptosis; Cathepsins; Dengue virus; Lysosome