COP9 signalosome interacts ATP-dependently with p97/valosin-containing protein (VCP) and controls the ubiquitination status of proteins bound to p97/VCP.
Ubiquitinated proteins can alternatively be delivered directly to the proteasome or via p97/VCP (valosin-containing protein). Whereas the proteasome degrades ubiquitinated proteins, the homohexameric ATPase p97/VCP seems to control the ubiquitination status of recruited substrates. The COP9 signalosome (CSN) is also involved in the ubiquitin/proteasome system (UPS) as exemplified by regulating the neddylation of ubiquitin E3 ligases. Here, we show that p97/VCP colocalizes and directly interacts with subunit 5 of the CSN (CSN5) in vivo and is associated with the entire CSN complex in an ATP-dependent manner. Furthermore, we provide evidence that the CSN and in particular the isopeptidase activity of its subunit CSN5 as well as the associated deubiquitinase USP15 are required for proper processing of polyubiquitinated substrates bound to p97/VCP. Moreover, we show that in addition to NEDD8, CSN5 binds to oligoubiquitin chains in vitro. Therefore, CSN and p97/VCP could form an ATP-dependent complex that resembles the 19 S proteasome regulatory particle and serves as a key mediator between ubiquitination and degradation pathways.
Cayli
Sevil
S
Unit of Reproductive Biology, Department of Anatomy and Cell Biology, Justus-Liebig-University, 35385 Giessen, Germany.
Klug
Jörg
J
Chapiro
Julius
J
Fröhlich
Suada
S
Krasteva
Gabriela
G
Orel
Lukas
L
Meinhardt
Andreas
A
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000075686:COP9 Signalosome Complex; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D046912:Multiprotein Complexes; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D000255:Adenosine Triphosphate; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse