Docking-dependent ubiquitination of the interferon regulatory factor-1 tumor suppressor protein by the ubiquitin ligase CHIP.
Characteristically for a regulatory protein, the IRF-1 tumor suppressor turns over rapidly with a half-life of between 20-40 min. This allows IRF-1 to reach new steady state protein levels swiftly in response to changing environmental conditions. Whereas CHIP (C terminus of Hsc70-interacting protein), appears to chaperone IRF-1 in unstressed cells, formation of a stable IRF-1·CHIP complex is seen under specific stress conditions. Complex formation, in heat- or heavy metal-treated cells, is accompanied by a decrease in IRF-1 steady state levels and an increase in IRF-1 ubiquitination. CHIP binds directly to an intrinsically disordered domain in the central region of IRF-1 (residues 106-140), and this site is sufficient to form a stable complex with CHIP in cells and to compete in trans with full-length IRF-1, leading to a reduction in its ubiquitination. The study reveals a complex relationship between CHIP and IRF-1 and highlights the role that direct binding or "docking" of CHIP to its substrate(s) can play in its mechanism of action as an E3 ligase.
CRUK Interferon and Cell Signalling Group, Cell Signalling Unit, Institute of Genetics and Molecular Medicine, Crewe Road South, University of Edinburgh, Edinburgh EH4 2XR, United Kingdom.
Vikram
V
Narayan
Emmanuelle
E
Pion
Vivien
V
Landré
Petr
P
Müller
Kathryn L
KL
Ball
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000737:chemistry / Q000378:metabolism*; D019216:Metals, Heavy / Q000633:toxicity; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
D018840:HSP70 Heat-Shock Proteins; D050856:Interferon Regulatory Factor-1; D019216:Metals, Heavy; D010446:Peptide Fragments; D025521:Tumor Suppressor Proteins; C097308:UBE2D1 protein, human; C489963:UBE2E1 protein, human; D044763:Ubiquitin-Conjugating Enzymes; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases