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UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1 alpha accumulation

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UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1 alpha accumulation. / Bandau, Susanne; Knebel, Axel; Gage, Zoe O.; Wood, Nicola T.; Alexandru, Gabriela.

In: BMC Biology, Vol. 10, 36, 26.04.2012, p. -.

Research output: Contribution to journalArticle

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Bandau, S, Knebel, A, Gage, ZO, Wood, NT & Alexandru, G 2012, 'UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1 alpha accumulation' BMC Biology, vol 10, 36, pp. -., 10.1186/1741-7007-10-36

APA

Bandau, S., Knebel, A., Gage, Z. O., Wood, N. T., & Alexandru, G. (2012). UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1 alpha accumulation. BMC Biology, 10, -. [36]. 10.1186/1741-7007-10-36

Vancouver

Bandau S, Knebel A, Gage ZO, Wood NT, Alexandru G. UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1 alpha accumulation. BMC Biology. 2012 Apr 26;10:-. 36. Available from: 10.1186/1741-7007-10-36

Author

Bandau, Susanne; Knebel, Axel; Gage, Zoe O.; Wood, Nicola T.; Alexandru, Gabriela / UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1 alpha accumulation.

In: BMC Biology, Vol. 10, 36, 26.04.2012, p. -.

Research output: Contribution to journalArticle

Bibtex - Download

@article{f54215ebec3f4cf8b2d703c1e0b83ffe,
title = "UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1 alpha accumulation",
author = "Susanne Bandau and Axel Knebel and Gage, {Zoe O.} and Wood, {Nicola T.} and Gabriela Alexandru",
year = "2012",
doi = "10.1186/1741-7007-10-36",
volume = "10",
pages = "--",
journal = "BMC Biology",
issn = "1741-7007",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1 alpha accumulation

A1 - Bandau,Susanne

A1 - Knebel,Axel

A1 - Gage,Zoe O.

A1 - Wood,Nicola T.

A1 - Alexandru,Gabriela

AU - Bandau,Susanne

AU - Knebel,Axel

AU - Gage,Zoe O.

AU - Wood,Nicola T.

AU - Alexandru,Gabriela

PY - 2012/4/26

Y1 - 2012/4/26

N2 - <p>Background: The proteins from the UBA-UBX family interact with ubiquitylated proteins via their UBA domain and with p97 via their UBX domain, thereby acting as substrate-binding adaptors for the p97 ATPase. In particular, human UBXN7 ( also known as UBXD7) mediates p97 interaction with the transcription factor HIF1 alpha that is actively ubiquitylated in normoxic cells by a CUL2-based E3 ligase, CRL2. Mass spectrometry analysis of UBA-UBX protein immunoprecipitates showed that they interact with a multitude of E3 ubiquitin-ligases. Conspicuously, UBXN7 was most proficient in interacting with cullin-RING ligase subunits. We therefore set out to determine whether UBXN7 interaction with cullins was direct or mediated by its ubiquitylated targets bound to the UBA domain.</p><p>Results: 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 alpha, 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 alpha. Both of these effects are strictly UIM-dependent and occur only when UBXN7 contains an intact UIM motif. We also show that HIF1 alpha carrying long ubiquitin-chains can recruit alternative ubiquitin-receptors, lacking p97's ATP-dependent segregase activity.</p><p>Conclusions: 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 alpha. 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 alpha.</p>

AB - <p>Background: The proteins from the UBA-UBX family interact with ubiquitylated proteins via their UBA domain and with p97 via their UBX domain, thereby acting as substrate-binding adaptors for the p97 ATPase. In particular, human UBXN7 ( also known as UBXD7) mediates p97 interaction with the transcription factor HIF1 alpha that is actively ubiquitylated in normoxic cells by a CUL2-based E3 ligase, CRL2. Mass spectrometry analysis of UBA-UBX protein immunoprecipitates showed that they interact with a multitude of E3 ubiquitin-ligases. Conspicuously, UBXN7 was most proficient in interacting with cullin-RING ligase subunits. We therefore set out to determine whether UBXN7 interaction with cullins was direct or mediated by its ubiquitylated targets bound to the UBA domain.</p><p>Results: 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 alpha, 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 alpha. Both of these effects are strictly UIM-dependent and occur only when UBXN7 contains an intact UIM motif. We also show that HIF1 alpha carrying long ubiquitin-chains can recruit alternative ubiquitin-receptors, lacking p97's ATP-dependent segregase activity.</p><p>Conclusions: 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 alpha. 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 alpha.</p>

U2 - 10.1186/1741-7007-10-36

DO - 10.1186/1741-7007-10-36

M1 - Article

JO - BMC Biology

JF - BMC Biology

SN - 1741-7007

VL - 10

SP - -

ER -

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