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Nat Struct Mol Biol. 2016 Nov;23(11):958-964. doi: 10.1038/nsmb.3308. Epub 2016 Oct 10.

Regulation of CED-3 caspase localization and activation by C. elegans nuclear-membrane protein NPP-14.

Author information

1
School of Life Sciences, Tsinghua University, Beijing, China.
2
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, China.
3
Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, Colorado, USA.

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.

PMID:
27723735
PMCID:
PMC5484413
DOI:
10.1038/nsmb.3308
[Indexed for MEDLINE]
Free PMC Article

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