%0 Journal Article
%T UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1¦Á accumulation
%A Susanne Bandau
%A Axel Knebel
%A Zoe O Gage
%A Nicola T Wood
%A Gabriela Alexandru
%J BMC Biology
%D 2012
%I BioMed Central
%R 10.1186/1741-7007-10-36
%X We show that UBXN7 interaction with cullins is independent of ubiquitin- and substrate-binding. Instead, it relies on the UIM motif in UBXN7 that directly engages the NEDD8 modification on cullins. To understand the functional consequences of UBXN7 interaction with neddylated cullins, we focused on HIF1¦Á, a CUL2 substrate that uses UBXD7/p97 as a ubiquitin-receptor on its way to proteasome-mediated degradation. We find that UBXN7 over-expression converts CUL2 to its neddylated form and causes the accumulation of non-ubiquitylated HIF1¦Á. Both of these effects are strictly UIM-dependent and occur only when UBXN7 contains an intact UIM motif. We also show that HIF1¦Á carrying long ubiquitin-chains can recruit alternative ubiquitin-receptors, lacking p97's ATP-dependent segregase activity.Our study shows that independently of its function as a ubiquitin-binding adaptor for p97, UBXN7 directly interacts with neddylated cullins and causes the accumulation of the CUL2 substrate HIF1¦Á. We propose that by sequestering CUL2 in its neddylated form, UBXN7 negatively regulates the ubiquitin-ligase activity of CRL2 and this might prevent recruitment of ubiquitin-receptors other than p97 to nuclear HIF1¦Á.Proteins destined for proteasome-mediated degradation are labeled with ubiquitin chains through the action of an enzymatic cascade consisting of a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-ligase (E3) [1]. Downstream of ubiquitylation, ubiquitin-receptors recognize the poly-ubiquitylated proteins and facilitate their degradation by the proteasome [2]. Some ubiquitin-receptors, such as PSMD4 (known as Rpn10 in yeast) and RPN13, are intrinsic to the regulatory particle of the proteasome [3,4]. Others, such as those from the RAD23 or ubiquilin families, shuttle on and off the proteasome [5]. In addition to the single subunit receptors mentioned above, a distinct class of ubiquitin-receptors endowed with ATPase activity has at its core p97 h
%K cullin
%K NEDD8
%K p97
%K ubiquitin-dependent degradation
%K UBXD7
%U http://www.biomedcentral.com/1741-7007/10/36