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

BMC Cell Biology

Rasmus Hartmann-Petersen²  Franziska Kriegenburg²  Rey-Huei Chen³  Chen-Ying Chien³  Michael Seeger⁴  Kay Hofmann⁵  Peter S Walmod¹  Esben G Poulsen²  Sofie V Nielsen²  Ida B Larsen²  Karen Molbæk²  Louise Madsen² 

[1] Department of Neuroscience and Pharmacology, University of Copenhagen, Symbion, Box 39, Fruebjergvej 3, Copenhagen Ø DK-2100, Denmark;Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen N DK-2200, Denmark;Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan;Institute for Biochemistry, Charité Universitätsmedizin, Berlin D-10117, Germany;Institute for Genetics, University of Cologne, Cologne D-50674, Germany

关键词: Degradation;    Chaperone;    Proteasome;    Ubiquitin;   

Others  :  1088725
DOI  :  10.1186/1471-2121-15-31

 received in 2014-05-08, accepted in 2014-07-23,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Madsen et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Ladanyi M, Lui MY, Antonescu CR, Krause-Boehm A, Meindl A, Argani P, Healey JH, Ueda T, Yoshikawa H, Meloni-Ehrig A, Sorensen PH, Mertens F, Mandahl N, van den Berghe H, Sciot R, Dal CP, Bridge J: The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene 2001, 20:48-57.
• [2]Bogan JS, Hendon N, McKee AE, Tsao TS, Lodish HF: Functional cloning of TUG as a regulator of GLUT4 glucose transporter trafficking. Nature 2003, 425:727-733.
• [3]Yu C, Cresswell J, Loffler MG, Bogan JS: The glucose transporter 4-regulating protein TUG is essential for highly insulin-responsive glucose uptake in 3 T3-L1 adipocytes. J Biol Chem 2007, 282:7710-7722.
• [4]Orme CM, Bogan JS: The UBX domain-containing protein TUG regulates the p97 ATPase and resides at the endoplasmic reticulum - Golgi intermediate compartment. J Biol Chem 2012, 287:6679-6692.
• [5]Schauber C, Chen L, Tongaonkar P, Vega I, Lambertson D, Potts W, Madura K: Rad23 links DNA repair to the ubiquitin/proteasome pathway. Nature 1998, 391:715-718.
• [6]Schuberth C, Buchberger A: UBX domain proteins: major regulators of the AAA ATPase Cdc48/p97. Cell Mol Life Sci 2008, 65:2360-2371.
• [7]Tettamanzi MC, Yu C, Bogan JS, Hodsdon ME: Solution structure and backbone dynamics of an N-terminal ubiquitin-like domain in the GLUT4-regulating protein, TUG. Protein Sci 2006, 15:498-508.
• [8]Arndt V, Rogon C, Hohfeld J: To be, or not to be–molecular chaperones in protein degradation. Cell Mol Life Sci 2007, 64:2525-2541.
• [9]Wilkinson CR, Seeger M, Hartmann-Petersen R, Stone M, Wallace M, Semple C, Gordon C: Proteins containing the UBA domain are able to bind to multi-ubiquitin chains. Nat Cell Biol 2001, 3:939-943.
• [10]Madsen L, Schulze A, Seeger M, Hartmann-Petersen R: Ubiquitin domain proteins in disease. BMC Biochem 2007, 8(1):S1.
• [11]Trempe JF, Chen CX, Grenier K, Camacho EM, Kozlov G, McPherson PS, Gehring K, Fon EA: SH3 domains from a subset of BAR proteins define a Ubl-binding domain and implicate parkin in synaptic ubiquitination. Mol Cell 2009, 36:1034-1047.
• [12]Bogan JS, Rubin BR, Yu C, Loffler MG, Orme CM, Belman JP, McNally LJ, Hao M, Cresswell JA: Endoproteolytic Cleavage of TUG Protein Regulates GLUT4 Glucose Transporter Translocation. J Biol Chem 2012, 287:23932-23947.
• [13]Buchberger A, Howard MJ, Proctor M, Bycroft M: The UBX domain: a widespread ubiquitin-like module. J Mol Biol 2001, 307:17-24.
• [14]Schuberth C, Richly H, Rumpf S, Buchberger A: Shp1 and Ubx2 are adaptors of Cdc48 involved in ubiquitin-dependent protein degradation. EMBO Rep 2004, 5:818-824.
• [15]Alexandru G, Graumann J, Smith GT, Kolawa NJ, Fang R, Deshaies RJ: UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover. Cell 2008, 134:804-816.
• [16]Zhao C, Slevin JT, Whiteheart SW: Cellular functions of NSF: not just SNAPs and SNAREs. FEBS Lett 2007, 581:2140-2149.
• [17]Bays NW, Wilhovsky SK, Goradia A, Hodgkiss-Harlow K, Hampton RY: HRD4/NPL4 is required for the proteasomal processing of ubiquitinated ER proteins. Mol Biol Cell 2001, 12:4114-4128.
• [18]Ye Y, Meyer HH, Rapoport TA: The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 2001, 414:652-656.
• [19]Braun S, Matuschewski K, Rape M, Thoms S, Jentsch S: Role of the ubiquitin-selective CDC48(UFD1/NPL4)chaperone (segregase) in ERAD of OLE1 and other substrates. EMBO J 2002, 21:615-621.
• [20]Jarosch E, Geiss-Friedlander R, Meusser B, Walter J, Sommer T: Protein dislocation from the endoplasmic reticulum–pulling out the suspect. Traffic 2002, 3:530-536.
• [21]Rabinovich E, Kerem A, Frohlich KU, Diamant N, Bar-Nun S: AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol Cell Biol 2002, 22:626-634.
• [22]Pye VE, Dreveny I, Briggs LC, Sands C, Beuron F, Zhang X, Freemont PS: Going through the motions: the ATPase cycle of p97. J Struct Biol 2006, 156:12-28.
• [23]Beuron F, Dreveny I, Yuan X, Pye VE, McKeown C, Briggs LC, Cliff MJ, Kaneko Y, Wallis R, Isaacson RL, Ladbury JE, Matthews SJ, Kondo H, Zhang X, Freemont PS: Conformational changes in the AAA ATPase p97-p47 adaptor complex. EMBO J 2006, 25:1967-1976.
• [24]Jentsch S, Rumpf S: Cdc48 (p97): a "molecular gearbox" in the ubiquitin pathway? Trends Biochem Sci 2007, 32:6-11.
• [25]Rape M, Hoppe T, Gorr I, Kalocay M, Richly H, Jentsch S: Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48(UFD1/NPL4), a ubiquitin-selective chaperone. Cell 2001, 107:667-677.
• [26]Kondo H, Rabouille C, Newman R, Levine TP, Pappin D, Freemont P, Warren G: p47 is a cofactor for p97-mediated membrane fusion. Nature 1997, 388:75-78.
• [27]Jarosch E, Taxis C, Volkwein C, Bordallo J, Finley D, Wolf DH, Sommer T: Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat Cell Biol 2002, 4:134-139.
• [28]Janiesch PC, Kim J, Mouysset J, Barikbin R, Lochmuller H, Cassata G, Krause S, Hoppe T: The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy. Nat Cell Biol 2007, 9:379-390.
• [29]Hoppe T, Matuschewski K, Rape M, Schlenker S, Ulrich HD, Jentsch S: Activation of a membrane-bound transcription factor by regulated ubiquitin/proteasome-dependent processing. Cell 2000, 102:577-586.
• [30]Madsen L, Seeger M, Semple CA, Hartmann-Petersen R: New ATPase regulators–p97 goes to the PUB. Int J Biochem Cell Biol 2009, 41:2380-2388.
• [31]Bandau S, Knebel A, Gage ZO, Wood NT, Alexandru G: UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1alpha accumulation. BMC Biol 2012, 10:36.
• [32]Buchberger A, Bukau B, Sommer T: Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms. Mol Cell 2010, 40:238-252.
• [33]Stolz A, Hilt W, Buchberger A, Wolf DH: Cdc48: a power machine in protein degradation. Trends Biochem Sci 2011, 36:515-523.
• [34]Vembar SS, Brodsky JL: One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 2008, 9:944-957.
• [35]Alberts SM, Sonntag C, Schafer A, Wolf DH: Ubx4 modulates cdc48 activity and influences degradation of misfolded proteins of the endoplasmic reticulum. J Biol Chem 2009, 284:16082-16089.
• [36]Verma R, Oania R, Fang R, Smith GT, Deshaies RJ: Cdc48/p97 mediates UV-dependent turnover of RNA Pol II. Mol Cell 2011, 41:82-92.
• [37]Chien CY, Chen RH: Cdc48 chaperone and adaptor ubx4 distribute the proteasome in the nucleus for anaphase proteolysis. J Biol Chem 2013, 288:37180-37191.
• [38]Madsen L, Andersen KM, Prag S, Moos T, Semple CA, Seeger M, Hartmann-Petersen R: Ubxd1 is a novel co-factor of the human p97 ATPase. Int J Biochem Cell Biol 2008, 40:2927-2942.
• [39]Madsen L, Kriegenburg F, Vala A, Best D, Prag S, Hofmann K, Seeger M, Adams IR, Hartmann-Petersen R: The tissue-specific Rep8/UBXD6 tethers p97 to the endoplasmic reticulum membrane for degradation of misfolded proteins. PLoS One 2011, 6:e25061.
• [40]Rancour DM, Park S, Knight SD, Bednarek SY: Plant UBX domain-containing protein 1, PUX1, regulates the oligomeric structure and activity of arabidopsis CDC48. J Biol Chem 2004, 279:54264-54274.
• [41]Park S, Rancour DM, Bednarek SY: Protein domain-domain interactions and requirements for the negative regulation of Arabidopsis CDC48/p97 by the plant ubiquitin regulatory X (UBX) domain-containing protein, PUX1. J Biol Chem 2007, 282:5217-5224.
• [42]Brooks P, Fuertes G, Murray RZ, Bose S, Knecht E, Rechsteiner MC, Hendil KB, Tanaka K, Dyson J, Rivett J: Subcellular localization of proteasomes and their regulatory complexes in mammalian cells. Biochem J 2000, 346(Pt 1):155-161.
• [43]Enenkel C, Lehmann A, Kloetzel PM: Subcellular distribution of proteasomes implicates a major location of protein degradation in the nuclear envelope-ER network in yeast. EMBO J 1998, 17:6144-6154.
• [44]Menendez-Benito V, Verhoef LG, Masucci MG, Dantuma NP: Endoplasmic reticulum stress compromises the ubiquitin-proteasome system. Hum Mol Genet 2005, 14:2787-2799.
• [45]Lass A, Kujawa M, McConnell E, Paton AW, Paton JC, Wojcik C: Decreased ER-associated degradation of alpha-TCR induced by Grp78 depletion with the SubAB cytotoxin. Int J Biochem Cell Biol 2008, 40:2865-2879.
• [46]Hartmann-Petersen R, Wallace M, Hofmann K, Koch G, Johnsen AH, Hendil KB, Gordon C: The Ubx2 and Ubx3 cofactors direct Cdc48 activity to proteolytic and nonproteolytic ubiquitin-dependent processes. Curr Biol 2004, 14:824-828.
• [47]Schulze A, Standera S, Buerger E, Kikkert M, Van VS, Wiertz E, Koning F, Kloetzel PM, Seeger M: The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway. J Mol Biol 2005, 354:1021-1027.
• [48]Jorgensen JP, Lauridsen AM, Kristensen P, Dissing K, Johnsen AH, Hendil KB, Hartmann-Petersen R: Adrm1, a putative cell adhesion regulating protein, is a novel proteasome-associated factor. J Mol Biol 2006, 360:1043-1052.