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Open Access Research article

Human ASPL/TUG interacts with p97 and complements the proteasome mislocalization of a yeast ubx4 mutant, but not the ER-associated degradation defect

Louise Madsen1, Karen Molbæk1, Ida B Larsen1, Sofie V Nielsen1, Esben G Poulsen1, Peter S Walmod2, Kay Hofmann3, Michael Seeger4, Chen-Ying Chien5, Rey-Huei Chen5, Franziska Kriegenburg1* and Rasmus Hartmann-Petersen1*

Author Affiliations

1 Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen N DK-2200, Denmark

2 Department of Neuroscience and Pharmacology, University of Copenhagen, Symbion, Box 39, Fruebjergvej 3, Copenhagen Ø DK-2100, Denmark

3 Institute for Genetics, University of Cologne, Cologne D-50674, Germany

4 Institute for Biochemistry, Charité Universitätsmedizin, Berlin D-10117, Germany

5 Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan

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BMC Cell Biology 2014, 15:31  doi:10.1186/1471-2121-15-31

Published: 31 July 2014

Abstract

Background

In mammalian cells, ASPL is involved in insulin-stimulated redistribution of the glucose transporter GLUT4 and assembly of the Golgi apparatus. Its putative yeast orthologue, Ubx4, is important for proteasome localization, endoplasmic reticulum-associated protein degradation (ERAD), and UV-induced degradation of RNA polymerase.

Results

Here, we show that ASPL is a cofactor of the hexameric ATPase complex, known as p97 or VCP in mammals and Cdc48 in yeast. In addition, ASPL interacts in vitro with NSF, another hexameric ATPase complex. ASPL localizes to the ER membrane. The central area in ASPL, containing both a SHP box and a UBX domain, is required for binding to the p97 N-domain. Knock-down of ASPL does not impair degradation of misfolded secretory proteins via the ERAD pathway. Deletion of UBX4 in yeast causes cycloheximide sensitivity, while ubx4 cdc48-3 double mutations cause proteasome mislocalization. ASPL alleviates these defects, but not the impaired ERAD.

Conclusions

In conclusion, ASPL and Ubx4 are homologous proteins with only partially overlapping functions. Both interact with p97/Cdc48, but while Ubx4 is important for ERAD, ASPL appears not to share this function.

Keywords:
Ubiquitin; Proteasome; Chaperone; Degradation