Processing of the ‘CaaX’ motif found on the C-termini of many proteins, including the proto-oncogene Ras, requires the ER (endoplasmic reticulum)-resident protease RCE1 (Ras-converting enzyme 1) and is necessary for the proper localization and function of many of these ‘CaaX’ proteins. In the present paper, we report that several mammalian species have a novel isoform (isoform 2) of RCE1 resulting from an alternate splice site and producing an N-terminally truncated protein. We demonstrate that both RCE1 isoform 1 and the newly identified isoform 2 are required to reinstate proper H-Ras processing and thus plasma membrane localization in RCE1-null cells. In addition, we show that the deubiquitinating enzyme USP17 (ubiquitin-specific protease 17), previously shown to modulate RCE1 activity, can regulate the abundance and localization of isoform 2. Furthermore, we show that isoform 2 is ubiquitinated on Lys43 and deubiquitinated by USP17. Collectively, the findings of the present study indicate that RCE1 isoform 2 is required for proper ‘CaaX’ processing and that USP17 can regulate this via its modulation of RCE1 isoform 2 ubiquitination.
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Research Article|
December 20 2013
A novel RCE1 isoform is required for H-Ras plasma membrane localization and is regulated by USP17
Jakub Jaworski;
Jakub Jaworski
*School of Pharmacy, Queen's University Belfast, McClay Research Building, 97 Lisburn Road, Belfast BT9 7BL, U.K.
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Ureshnie Govender;
Ureshnie Govender
*School of Pharmacy, Queen's University Belfast, McClay Research Building, 97 Lisburn Road, Belfast BT9 7BL, U.K.
†Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Health Sciences Building, 97 Lisburn Road, Belfast BT9 7BL, U.K.
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Cheryl McFarlane;
Cheryl McFarlane
†Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Health Sciences Building, 97 Lisburn Road, Belfast BT9 7BL, U.K.
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Michelle de la Vega;
Michelle de la Vega
†Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Health Sciences Building, 97 Lisburn Road, Belfast BT9 7BL, U.K.
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Michelle K. Greene;
Michelle K. Greene
*School of Pharmacy, Queen's University Belfast, McClay Research Building, 97 Lisburn Road, Belfast BT9 7BL, U.K.
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Neil D. Rawlings;
Neil D. Rawlings
‡Wellcome Trust Sanger Institute, Cambridge CB10 1SA, U.K.
§European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SD, U.K.
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James A. Johnston;
James A. Johnston
1
†Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Health Sciences Building, 97 Lisburn Road, Belfast BT9 7BL, U.K.
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Christopher J. Scott;
Christopher J. Scott
*School of Pharmacy, Queen's University Belfast, McClay Research Building, 97 Lisburn Road, Belfast BT9 7BL, U.K.
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James F. Burrows
James F. Burrows
2
*School of Pharmacy, Queen's University Belfast, McClay Research Building, 97 Lisburn Road, Belfast BT9 7BL, U.K.
2To whom correspondence should be addressed (email j.burrows@qub.ac.uk).
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Publisher: Portland Press Ltd
Received:
September 11 2013
Revision Received:
October 17 2013
Accepted:
October 17 2013
Accepted Manuscript online:
October 17 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 457 (2): 289–300.
Article history
Received:
September 11 2013
Revision Received:
October 17 2013
Accepted:
October 17 2013
Accepted Manuscript online:
October 17 2013
Citation
Jakub Jaworski, Ureshnie Govender, Cheryl McFarlane, Michelle de la Vega, Michelle K. Greene, Neil D. Rawlings, James A. Johnston, Christopher J. Scott, James F. Burrows; A novel RCE1 isoform is required for H-Ras plasma membrane localization and is regulated by USP17. Biochem J 15 January 2014; 457 (2): 289–300. doi: https://doi.org/10.1042/BJ20131213
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