Journal article
Fidgetin binds spastin to attenuate the microtubule-severing activity
Biochimica et biophysica acta. Molecular cell research, v 1872(2), 119890
Feb 2025
PMID: 39681249
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Microtubule-severing enzymes such as spastin, katanin, and fidgetin, characterized by their AAA ATPase domains, are pivotal in modulating microtubule dynamics and behavior across various cellular processes. While spastin and katanin are recognized for their predominant and robust severing of stable microtubules, thereby enhancing microtubule turnover, fidgetin exhibits comparatively weaker severing activity and selectively targets labile microtubules. The interplay among these enzymes and their mutual regulatory mechanisms remains inadequately understood. In this study, we elucidate the functional interaction between spastin and fidgetin, focusing on their roles in microtubule severing and neurite outgrowth. Our findings demonstrate that fidgetin serves as a negative regulator of spastin's severing activity. Co-expression assays revealed that fidgetin significantly attenuates spastin's severing efficiency, as confirmed by fluorescence-based microtubule polymerization assays and quantitative imaging of microtubule dynamics. Co-immunoprecipitation and Förster Resonance Energy Transfer (FRET) analyses further established a direct interaction between fidgetin and spastin, suggesting that fidgetin modulates spastin's activity through direct binding, possibly contributing to forming the hetero-hexmeric ring for their severing activities. Functionally, spastin overexpression in neuronal cells enhances neurite outgrowth, an effect that is suppressed upon co-expression with fidgetin, indicating that fidgetin counterbalances spastin's activity to regulate neurite extension. Therefore, this study uncovers a previously unrecognized mechanism by which fidgetin modulates spastin's function, providing critical insights into the intricate regulation of microtubule severing. These findings have significant implications for therapeutic strategies targeting microtubule-severing activities, particularly in neurodevelopmental and neurodegenerative disorders where microtubule dysregulation is a hallmark.
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Details
- Title
- Fidgetin binds spastin to attenuate the microtubule-severing activity
- Creators
- Ying Sun - Nantong UniversitySkandha Ramakrishnan - Drexel UniversityXiaona Lai - Nantong UniversityRonghua Wu - Nantong UniversityZhangji Dong - Nantong UniversityLiang Qiang - Drexel UniversityMei Liu - Nantong University
- Publication Details
- Biochimica et biophysica acta. Molecular cell research, v 1872(2), 119890
- Publisher
- Elsevier
- Number of pages
- 9
- Grant note
- National Natural Science Foundation of China: 32070725 Major Program of The Natural Science Foundation of the Jiangsu Higher Education Institutions: 23KJA180005 NIH/NINDS: R01NS115977 Spastic Paraplegia Foundation
The work was supported by the grants from the National Natural Science Foundation of China to ML (32070725) , the Major Program of The Natural Science Foundation of the Jiangsu Higher Education Institutions to ZD (23KJA180005) , and NIH/NINDS R01NS115977 to LQ and Spastic Paraplegia Foundation grant to LQ.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy; College of Medicine
- Web of Science ID
- WOS:001391339600001
- Scopus ID
- 2-s2.0-85212037036
- Other Identifier
- 991022005077704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology