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Published online December 31, 2007
doi:10.1083/jcb.200707063
The Journal of Cell Biology, Vol. 179, No. 7, 1453-1466
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Tait et al.
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Article

 Apoptosis induction by Bid requires unconventional ubiquitination and degradation of its N-terminal fragment

Stephen W.G. Tait1, Evert de Vries1, Chiel Maas1, Anna M. Keller1, Clive S. D'Santos2, and Jannie Borst1

1 Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands
2 Department of Biomolecular Mass Spectrometry, Utrecht University, 3584 CA Utrecht, Netherlands

Correspondence to Jannie Borst: j.borst{at}nki.nl

Bcl-2 family member Bid is subject to autoinhibition; in the absence of stimuli, its N-terminal region sequesters the proapoptotic Bcl-2 homology 3 (BH3) domain. Upon proteolytic cleavage in its unstructured loop, Bid is activated, although structural data reveal no apparent resulting conformational change. We found that, upon Bid cleavage, the N-terminal fragment (tBid-N) is ubiquitinated and degraded, thus freeing the BH3 domain in the C-terminal fragment (tBid-C). Ubiquitination of tBid-N is unconventional because acceptor sites are neither lysines nor the N terminus. Chemical approaches implicated thioester and hydroxyester linkage of ubiquitin and mutagenesis implicated serine and possibly threonine as acceptor residues in addition to cysteine. Acceptor sites reside predominantly but not exclusively in helix 1, which is required for ubiquitination and degradation of tBid-N. Rescue of tBid-N from degradation blocked Bid's ability to induce mitochondrial outer membrane permeability but not mitochondrial translocation of the cleaved complex. We conclude that unconventional ubiquitination and proteasome-dependent degradation of tBid-N is required to unleash the proapoptotic activity of tBid-C.

S.W.G. Tait's present address is Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.

C.S. D'Santos's present address is Proteomic Unit Bergen, University of Bergen, N-5009 Bergen, Norway.

Abbreviations used in this paper: BH, Bcl-2 homology; CHX, cycloheximide; CLSM, confocal laser scanning microscopy; Cyt c, cytochrome c; NMR, nuclear magnetic resonance; TAP, tandem affinity purification; tBid-C, C-terminal fragment of Bid; tBid-N, N-terminal fragment of Bid; TEV, tobacco etch virus; TRAIL, TNF-related apoptosis-inducing ligand; VSV, vesicular stomatitis virus.


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