Znf179 E3 ligase-mediated TDP-43 polyubiquitination is involved in TDP-43- ubiquitinated inclusions (UBI) (+)-related neurodegenerative pathology
Abstract Background The brain predominantly expressed RING finger protein, Znf179, is known to be important for embryonic neuronal differentiation during brain development. Downregulation of Znf179 has been observed in motor neurons of adult mouse models for amyotrophic lateral sclerosis (ALS), yet...
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| Format: | Article |
| Language: | English |
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BMC
2018-11-01
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| Series: | Journal of Biomedical Science |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12929-018-0479-4 |
| _version_ | 1819242156419710976 |
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| author | Yi-Chao Lee Wan-Chen Huang Jiann-Her Lin Tzu-Jen Kao Hui-Ching Lin Kuen-Haur Lee Hsin-Chuan Lin Che-Kun James Shen Wen-Chang Chang Chi-Chen Huang |
| author_facet | Yi-Chao Lee Wan-Chen Huang Jiann-Her Lin Tzu-Jen Kao Hui-Ching Lin Kuen-Haur Lee Hsin-Chuan Lin Che-Kun James Shen Wen-Chang Chang Chi-Chen Huang |
| author_sort | Yi-Chao Lee |
| collection | DOAJ |
| description | Abstract Background The brain predominantly expressed RING finger protein, Znf179, is known to be important for embryonic neuronal differentiation during brain development. Downregulation of Znf179 has been observed in motor neurons of adult mouse models for amyotrophic lateral sclerosis (ALS), yet the molecular function of Znf179 in neurodegeneration has never been previously described. Znf179 contains the classical C3HC4 RING finger domain, and numerous proteins containing C3HC4 RING finger domain act as E3 ubiquitin ligases. Hence, we are interested to identify whether Znf179 possesses E3 ligase activity and its role in ALS neuropathy. Methods We used in vivo and in vitro ubiquitination assay to examine the E3 ligase autoubiquitination activity of Znf179 and its effect on 26S proteasome activity. To search for the candidate substrates of Znf179, we immunoprecipitated Znf179 and subjected to mass spectrometry (MS) analysis to identify its interacting proteins. We found that ALS/ FTLD-U (frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions)-related neurodegenerative TDP-43 protein is the E3 ligase substrate of Znf179. To further clarify the role of E3 ubiquitin ligase Znf179 in neurodegenerative TDP-43-UBI (ubiquitinated inclusions) (+) proteinopathy, the effect of Znf179-mediated TDP-43 polyubiquitination on TDP-43 protein stability, aggregate formation and nucleus/cytoplasm mislocalization were evaluated in vitro cell culture system and in vivo animal model. Results Here we report that Znf179 is a RING E3 ubiquitin ligase which possesses autoubiquitination feature and regulates 26S proteasome activity through modulating the protein expression levels of 19S/20S proteasome subunits. Our immunoprecipitation assay and MS analysis results revealed that the neuropathological TDP-43 protein is one of its E3 ligase substrate. Znf179 interactes with TDP-43 protein and mediates polyubiquitination of TDP-43 in vitro and in vivo. In neurodegenerative TDP-43 proteinopathy, we found that Znf179-mediated polyubiquitination of TDP-43 accelerates its protein turnover rate and attenuates insoluble pathologic TDP-43 aggregates, while knockout of Znf179 in mouse brain results in accumulation of insoluble TDP-43 and cytosolic TDP-43 inclusions in cortex, hippocampus and midbrain regions. Conclusions Here we unveil the important role for the novel E3 ligase Znf179 in TDP-43-mediated neuropathy, and provide a potential therapeutic strategy for combating ALS/ FTLD-U neurodegenerative pathologies. |
| first_indexed | 2024-12-23T14:35:19Z |
| format | Article |
| id | doaj.art-7f3fe636c1a9433494d9cf7962b1d9ce |
| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-12-23T14:35:19Z |
| publishDate | 2018-11-01 |
| publisher | BMC |
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| series | Journal of Biomedical Science |
| spelling | doaj.art-7f3fe636c1a9433494d9cf7962b1d9ce2022-12-21T17:43:23ZengBMCJournal of Biomedical Science1423-01272018-11-0125111710.1186/s12929-018-0479-4Znf179 E3 ligase-mediated TDP-43 polyubiquitination is involved in TDP-43- ubiquitinated inclusions (UBI) (+)-related neurodegenerative pathologyYi-Chao Lee0Wan-Chen Huang1Jiann-Her Lin2Tzu-Jen Kao3Hui-Ching Lin4Kuen-Haur Lee5Hsin-Chuan Lin6Che-Kun James Shen7Wen-Chang Chang8Chi-Chen Huang9Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology/Center for Neurotrauma and Neuroregeneration, Taipei Medical UniversityInstitute of Cellular and Organismic Biology, Academia SinicaGraduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology/Center for Neurotrauma and Neuroregeneration, Taipei Medical UniversityGraduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology/Center for Neurotrauma and Neuroregeneration, Taipei Medical UniversityInstitute and Department of Physiology, School of Medicine, National Yang-Ming UniversityGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical UniversityGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityInstitute of Molecular Biology, Academia SinicaGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityGraduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology/Center for Neurotrauma and Neuroregeneration, Taipei Medical UniversityAbstract Background The brain predominantly expressed RING finger protein, Znf179, is known to be important for embryonic neuronal differentiation during brain development. Downregulation of Znf179 has been observed in motor neurons of adult mouse models for amyotrophic lateral sclerosis (ALS), yet the molecular function of Znf179 in neurodegeneration has never been previously described. Znf179 contains the classical C3HC4 RING finger domain, and numerous proteins containing C3HC4 RING finger domain act as E3 ubiquitin ligases. Hence, we are interested to identify whether Znf179 possesses E3 ligase activity and its role in ALS neuropathy. Methods We used in vivo and in vitro ubiquitination assay to examine the E3 ligase autoubiquitination activity of Znf179 and its effect on 26S proteasome activity. To search for the candidate substrates of Znf179, we immunoprecipitated Znf179 and subjected to mass spectrometry (MS) analysis to identify its interacting proteins. We found that ALS/ FTLD-U (frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions)-related neurodegenerative TDP-43 protein is the E3 ligase substrate of Znf179. To further clarify the role of E3 ubiquitin ligase Znf179 in neurodegenerative TDP-43-UBI (ubiquitinated inclusions) (+) proteinopathy, the effect of Znf179-mediated TDP-43 polyubiquitination on TDP-43 protein stability, aggregate formation and nucleus/cytoplasm mislocalization were evaluated in vitro cell culture system and in vivo animal model. Results Here we report that Znf179 is a RING E3 ubiquitin ligase which possesses autoubiquitination feature and regulates 26S proteasome activity through modulating the protein expression levels of 19S/20S proteasome subunits. Our immunoprecipitation assay and MS analysis results revealed that the neuropathological TDP-43 protein is one of its E3 ligase substrate. Znf179 interactes with TDP-43 protein and mediates polyubiquitination of TDP-43 in vitro and in vivo. In neurodegenerative TDP-43 proteinopathy, we found that Znf179-mediated polyubiquitination of TDP-43 accelerates its protein turnover rate and attenuates insoluble pathologic TDP-43 aggregates, while knockout of Znf179 in mouse brain results in accumulation of insoluble TDP-43 and cytosolic TDP-43 inclusions in cortex, hippocampus and midbrain regions. Conclusions Here we unveil the important role for the novel E3 ligase Znf179 in TDP-43-mediated neuropathy, and provide a potential therapeutic strategy for combating ALS/ FTLD-U neurodegenerative pathologies.http://link.springer.com/article/10.1186/s12929-018-0479-4Znf179TDP-43PolyubiquitinationE3 ligaseALSFTLD-U |
| spellingShingle | Yi-Chao Lee Wan-Chen Huang Jiann-Her Lin Tzu-Jen Kao Hui-Ching Lin Kuen-Haur Lee Hsin-Chuan Lin Che-Kun James Shen Wen-Chang Chang Chi-Chen Huang Znf179 E3 ligase-mediated TDP-43 polyubiquitination is involved in TDP-43- ubiquitinated inclusions (UBI) (+)-related neurodegenerative pathology Journal of Biomedical Science Znf179 TDP-43 Polyubiquitination E3 ligase ALS FTLD-U |
| title | Znf179 E3 ligase-mediated TDP-43 polyubiquitination is involved in TDP-43- ubiquitinated inclusions (UBI) (+)-related neurodegenerative pathology |
| title_full | Znf179 E3 ligase-mediated TDP-43 polyubiquitination is involved in TDP-43- ubiquitinated inclusions (UBI) (+)-related neurodegenerative pathology |
| title_fullStr | Znf179 E3 ligase-mediated TDP-43 polyubiquitination is involved in TDP-43- ubiquitinated inclusions (UBI) (+)-related neurodegenerative pathology |
| title_full_unstemmed | Znf179 E3 ligase-mediated TDP-43 polyubiquitination is involved in TDP-43- ubiquitinated inclusions (UBI) (+)-related neurodegenerative pathology |
| title_short | Znf179 E3 ligase-mediated TDP-43 polyubiquitination is involved in TDP-43- ubiquitinated inclusions (UBI) (+)-related neurodegenerative pathology |
| title_sort | znf179 e3 ligase mediated tdp 43 polyubiquitination is involved in tdp 43 ubiquitinated inclusions ubi related neurodegenerative pathology |
| topic | Znf179 TDP-43 Polyubiquitination E3 ligase ALS FTLD-U |
| url | http://link.springer.com/article/10.1186/s12929-018-0479-4 |
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