Journal article
JosD1, a Membrane-targeted Deubiquitinating Enzyme, Is Activated by Ubiquitination and Regulates Membrane Dynamics, Cell Motility, and Endocytosis
The Journal of biological chemistry, Vol.288(24), pp.17145-17155
06/14/2013
DOI: 10.1074/jbc.M113.463406
PMCID: PMC3682520
PMID: 23625928
Abstract
The functional diversity of deubiquitinating enzymes (DUBs) is not well understood. The MJD family of DUBs consists of four cysteine proteases that share a catalytic “Josephin” domain. The family is named after the DUB ATXN3, which causes the neurodegenerative disease Machado-Joseph disease. The two closely related Josephin domain-containing (JosD) proteins 1 and 2 consist of little more than the Josephin domain. To gain insight into the properties of Josephin domains, we investigated JosD1 and JosD2. JosD1 and JosD2 were found to differ fundamentally in many respects. In vitro, only JosD2 can cleave ubiquitin chains. In contrast, JosD1 cleaves ubiquitin chains only after it is monoubiquitinated, a form of posttranslational-dependent regulation shared with ATXN3. A significant fraction of JosD1 is monoubiquitinated in diverse mouse tissues. In cell-based studies, JosD2 localizes to the cytoplasm whereas JosD1 preferentially localizes to the plasma membrane, particularly when ubiquitinated. The membrane occupancy by JosD1 suggests that it could participate in membrane-dependent events such as cell motility and endocytosis. Indeed, time-lapse imaging revealed that JosD1 enhances membrane dynamics and cell motility. JosD1 also influences endocytosis in cultured cells by increasing the uptake of endocytic markers of macropinocytosis while decreasing those for clathrin- and caveolae-mediated endocytosis. Our results establish that two closely related DUBs differ markedly in activity and function and that JosD1, a membrane-associated DUB whose activity is regulated by ubiquitination, helps regulate membrane dynamics, cell motility, and endocytosis.
Background: The functions of the deubiquitinating enzymes JosD1 and JosD2, related to ATXN3, are unknown.
Results: JosD1 is activated by ubiquitination, localizes to plasma membrane, and affects membrane dynamics, cell motility, and endocytosis.
Conclusion: JosD1 and JosD2 possess divergent properties, with JosD1 regulating membrane-related functions.
Significance: Our findings provide insight into diverse functions of a disease-linked family of deubiquitinating enzymes.
Details
- Title: Subtitle
- JosD1, a Membrane-targeted Deubiquitinating Enzyme, Is Activated by Ubiquitination and Regulates Membrane Dynamics, Cell Motility, and Endocytosis
- Creators
- Takahiro Seki - From the Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109Lijie Gong - From the Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109Aislinn J Williams - the Program in Neuroscience and Medical Scientist Training Program, University of Iowa, Iowa City, Iowa 52242, andNorio Sakai - the Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, JapanSokol V Todi - the Departments of Pharmacology and Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201Henry L Paulson - From the Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.288(24), pp.17145-17155
- DOI
- 10.1074/jbc.M113.463406
- PMID
- 23625928
- PMCID
- PMC3682520
- NLM abbreviation
- J Biol Chem
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 06/14/2013
- Academic Unit
- Psychiatry; Iowa Neuroscience Institute
- Record Identifier
- 9984065834502771
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