BCL-3 degradation involves its polyubiquitination through a FBW7-independent pathway and its binding to the proteasome subunit PSMB1.
The oncogenic protein BCL-3 activates or represses gene transcription through binding with the NF-kappaB proteins p50 and p52 and is degraded through a phospho- and GSK3-dependent pathway. However, the mechanisms underlying its degradation remain poorly understood. Yeast two-hybrid analysis led to the identification of the proteasome subunit PSMB1 as a BCL-3-associated protein. The binding of BCL-3 to PSMB1 is required for its degradation through the proteasome. Indeed, PSMB1-depleted cells are defective in degrading polyubiquitinated BCL-3. The N-terminal part of BCL-3 includes lysines 13 and 26 required for the Lys(48)-linked polyubiquitination of BCL-3. Moreover, the E3 ligase FBW7, known to polyubiquitinate a variety of substrates phosphorylated by GSK3, is dispensable for BCL-3 degradation. Thus, our data defined a unique motif of BCL-3 that is needed for its recruitment to the proteasome and identified PSMB1 as a key protein required for the proteasome-mediated degradation of a nuclear and oncogenic IkappaB protein.
Keutgens
Aurore
A
Interdisciplinary Cluster for Applied Genoproteomics, GIGA-Research, Unit of Medical Chemistry, Department of Infectious and Parasitic Diseases, Faculty of Veterinary Medicine, University of Liège, Sart-Tilman, 4000 Liège, Belgium.
Zhang
Xin
X
Shostak
Kateryna
K
Robert
Isabelle
I
Olivier
Sabine
S
Vanderplasschen
Alain
A
Chapelle
Jean-Paul
JP
Viatour
Patrick
P
Merville
Marie-Paule
MP
Bex
Françoise
F
Gothot
André
A
Chariot
Alain
A
D000081242:B-Cell Lymphoma 3 Protein; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D008239:Lysine / Q000378:metabolism; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics / Q000502:physiology
D000081242:B-Cell Lymphoma 3 Protein; C000631344:BCL3 protein, human; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D008239:Lysine