Cell
Volume 134, Issue 4, 22 August 2008, Pages 668-678
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Ubiquitin Chain Editing Revealed by Polyubiquitin Linkage-Specific Antibodies

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Summary

Posttranslational modification of proteins with polyubiquitin occurs in diverse signaling pathways and is tightly regulated to ensure cellular homeostasis. Studies employing ubiquitin mutants suggest that the fate of polyubiquitinated proteins is determined by which lysine within ubiquitin is linked to the C terminus of an adjacent ubiquitin. We have developed linkage-specific antibodies that recognize polyubiquitin chains joined through lysine 63 (K63) or 48 (K48). A cocrystal structure of an anti-K63 linkage Fab bound to K63-linked diubiquitin provides insight into the molecular basis for specificity. We use these antibodies to demonstrate that RIP1, which is essential for tumor necrosis factor-induced NF-κB activation, and IRAK1, which participates in signaling by interleukin-1β and Toll-like receptors, both undergo polyubiquitin editing in stimulated cells. Both kinase adaptors initially acquire K63-linked polyubiquitin, while at later times K48-linked polyubiquitin targets them for proteasomal degradation. Polyubiquitin editing may therefore be a general mechanism for attenuating innate immune signaling.

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6

Present address: Ammunix, Inc., 500 Ellis Street, Suite B, Mountain View, CA 94043, USA

7

Present address: Terrence Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada

8

Present address: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada

9

Present address: General Biologic, 169 Mengzi Road, Suite 301, Building 2, Shanghai, 200023 PR China