title: Regulation of CED-3 caspase localization and activation by C. elegans nuclear-membrane protein NPP-14.
abstract: Caspases are cysteine proteases with critical roles in apoptosis. The Caenorhabditis elegans caspase CED-3 is activated by autocatalytic cleavage, a process enhanced by CED-4. Here we report that the CED-3 zymogen localizes to the perinuclear region in C. elegans germ cells and that CED-3 autocatalytic cleavage is held in check by C. elegans nuclei and activated by CED-4. The nuclear-pore protein NPP-14 interacts with the CED-3 zymogen prodomain, colocalizes with CED-3 in vivo and inhibits CED-3 autoactivation in vitro. Several missense mutations in the CED-3 prodomain result in stronger association with NPP-14 and decreased CED-3 activation by CED-4 in the presence of nuclei or NPP-14, thus leading to cell-death defects. Those same mutations enhance autocatalytic cleavage of CED-3 in vitro and increase apoptosis in vivo in the absence of npp-14. Our results reveal a critical role of nuclei and nuclear-membrane proteins in regulating the activation and localization of CED-3.
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, USA.
authors.forename: Yu-Zen
authors.initials: YZ
authors.lastname: Chen
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: Harry
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, USA.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Nakagawa
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, USA.
authors.forename: Eui-Seung
authors.initials: ES
authors.lastname: Lee
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Guo
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, China.|Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: Xue
mesh_terms: D000818:Animals; D017209:Apoptosis; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D020125:Mutation, Missense; D028861:Nuclear Pore Complex Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs
chemical_list: D029742:Caenorhabditis elegans Proteins; C000618734:NPP-14 protein, C elegans; D028861:Nuclear Pore Complex Proteins; D020169:Caspases; C089223:ced-3 protein, C elegans