Granulysin induces cathepsin B release from lysosomes of target tumor cells to attack mitochondria through processing of bid leading to Necroptosis.
Granulysin is a killer effector molecule localized in cytolytic granules of human NK and CTL cells. Granulysin exhibits broad antimicrobial activity and potent cytotoxic action against tumor cells. However, the molecular mechanism of granulysin-induced tumor lysis is poorly understood. In this study, we found that granulysin causes a novel cell death termed necroptosis. Granulysin can target lysosomes of target tumor cells and induce partial release of lysosomal contents into the cytosol. Relocalized lysosomal cathepsin B can process Bid to active tBid to cause cytochrome c and apoptosis-activating factor release from mitochondria. Cathepsin B silencing and Bid or Bax/Bak deficiency resists granulysin-induced cytochrome c and apoptosis-activating factor release and is less susceptible to cytolysis against target tumor cells.
Zhang
Honglian
H
National Laboratory of Biomacromolecules and Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Zhong
Chao
C
Shi
Lei
L
Guo
Yuming
Y
Fan
Zusen
Z
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D002401:Cathepsin B / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology
D000945:Antigens, Differentiation, T-Lymphocyte; D051023:BH3 Interacting Domain Death Agonist Protein; C075005:GNLY protein, human; D045304:Cytochromes c; D002401:Cathepsin B