Drosophila ubiquitin-specific peptidase 14 stabilizes the PERIOD protein by regulating a ubiquitin ligase SLIMB
Abstract The circadian clock orchestrates behavior and physiology through the oscillation of key clock proteins like PERIOD (PER). Here, we investigate the role of ubiquitin-specific peptidase 14 (USP14) in modulating PER stability and circadian rhythms in Drosophila. We find that overexpression of...
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Nature Portfolio
2025-02-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07632-9 |
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| author | So Who Kang Jung-Eun Park Soonhyuck Ok Minhui Um Hyeonjeong Son Seunghee Byun Nayoung Park Su Jin Lee Thị Xuân Thùy Trần Gyeongmin Kim Jeonghun Yeom Kyunggon Kim Eun Young Kim Min-Ji Kang |
| author_facet | So Who Kang Jung-Eun Park Soonhyuck Ok Minhui Um Hyeonjeong Son Seunghee Byun Nayoung Park Su Jin Lee Thị Xuân Thùy Trần Gyeongmin Kim Jeonghun Yeom Kyunggon Kim Eun Young Kim Min-Ji Kang |
| author_sort | So Who Kang |
| collection | DOAJ |
| description | Abstract The circadian clock orchestrates behavior and physiology through the oscillation of key clock proteins like PERIOD (PER). Here, we investigate the role of ubiquitin-specific peptidase 14 (USP14) in modulating PER stability and circadian rhythms in Drosophila. We find that overexpression of USP14 in clock cells reduces PER protein levels without altering its mRNA levels whereas USP14 knockdown increases PER protein levels, suggesting that USP14 regulates PER post-translationally. Interestingly, despite these alterations in PER levels, neither USP14 overexpression nor knockdown significantly impacts circadian behavioral rhythms, likely because of slight effects on PER levels in small ventral lateral neurons (sLNvs). Further analysis shows that USP14 physically interacts with Supernumerary Limbs (SLIMB), a protein involved in PER degradation. Moreover, reducing slimb expression mitigates the effects of USP14 on PER protein stability. Mass spectrometry identifies two ubiquitination sites on PER (Lys1117 and Lys1118) critical for its degradation. Expression of PER1117A, 1118A mutant in per 01 background impairs circadian rhythm strength. In conclusion, this study demonstrates that Drosophila USP14 indirectly modulates PER protein stability by affecting SLIMB and highlights the critical role of specific ubiquitination sites on PER in maintaining circadian rhythms. |
| format | Article |
| id | doaj-art-492e27249fc94a03b51990b03051409a |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-492e27249fc94a03b51990b03051409a2025-02-09T12:50:45ZengNature PortfolioCommunications Biology2399-36422025-02-018111010.1038/s42003-025-07632-9Drosophila ubiquitin-specific peptidase 14 stabilizes the PERIOD protein by regulating a ubiquitin ligase SLIMBSo Who Kang0Jung-Eun Park1Soonhyuck Ok2Minhui Um3Hyeonjeong Son4Seunghee Byun5Nayoung Park6Su Jin Lee7Thị Xuân Thùy Trần8Gyeongmin Kim9Jeonghun Yeom10Kyunggon Kim11Eun Young Kim12Min-Ji Kang13Department of Biomedical Sciences, Ajou University Graduate School of MedicineDepartment of Pharmacology, Brain Korea 21 Project, University of Ulsan College of Medicine, Asan Medical CenterDepartment of Pharmacology, Brain Korea 21 Project, University of Ulsan College of Medicine, Asan Medical CenterDepartment of Pharmacology, Brain Korea 21 Project, University of Ulsan College of Medicine, Asan Medical CenterDepartment of Pharmacology, Brain Korea 21 Project, University of Ulsan College of Medicine, Asan Medical CenterDepartment of Pharmacology, Brain Korea 21 Project, University of Ulsan College of Medicine, Asan Medical CenterDepartment of Pharmacology, Brain Korea 21 Project, University of Ulsan College of Medicine, Asan Medical CenterDepartment of Pharmacology, Brain Korea 21 Project, University of Ulsan College of Medicine, Asan Medical CenterDepartment of Pharmacology, Brain Korea 21 Project, University of Ulsan College of Medicine, Asan Medical CenterDepartment of Pharmacology, Brain Korea 21 Project, University of Ulsan College of Medicine, Asan Medical CenterConvergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical CenterConvergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical CenterDepartment of Biomedical Sciences, Ajou University Graduate School of MedicineDepartment of Pharmacology, Brain Korea 21 Project, University of Ulsan College of Medicine, Asan Medical CenterAbstract The circadian clock orchestrates behavior and physiology through the oscillation of key clock proteins like PERIOD (PER). Here, we investigate the role of ubiquitin-specific peptidase 14 (USP14) in modulating PER stability and circadian rhythms in Drosophila. We find that overexpression of USP14 in clock cells reduces PER protein levels without altering its mRNA levels whereas USP14 knockdown increases PER protein levels, suggesting that USP14 regulates PER post-translationally. Interestingly, despite these alterations in PER levels, neither USP14 overexpression nor knockdown significantly impacts circadian behavioral rhythms, likely because of slight effects on PER levels in small ventral lateral neurons (sLNvs). Further analysis shows that USP14 physically interacts with Supernumerary Limbs (SLIMB), a protein involved in PER degradation. Moreover, reducing slimb expression mitigates the effects of USP14 on PER protein stability. Mass spectrometry identifies two ubiquitination sites on PER (Lys1117 and Lys1118) critical for its degradation. Expression of PER1117A, 1118A mutant in per 01 background impairs circadian rhythm strength. In conclusion, this study demonstrates that Drosophila USP14 indirectly modulates PER protein stability by affecting SLIMB and highlights the critical role of specific ubiquitination sites on PER in maintaining circadian rhythms.https://doi.org/10.1038/s42003-025-07632-9 |
| spellingShingle | So Who Kang Jung-Eun Park Soonhyuck Ok Minhui Um Hyeonjeong Son Seunghee Byun Nayoung Park Su Jin Lee Thị Xuân Thùy Trần Gyeongmin Kim Jeonghun Yeom Kyunggon Kim Eun Young Kim Min-Ji Kang Drosophila ubiquitin-specific peptidase 14 stabilizes the PERIOD protein by regulating a ubiquitin ligase SLIMB Communications Biology |
| title | Drosophila ubiquitin-specific peptidase 14 stabilizes the PERIOD protein by regulating a ubiquitin ligase SLIMB |
| title_full | Drosophila ubiquitin-specific peptidase 14 stabilizes the PERIOD protein by regulating a ubiquitin ligase SLIMB |
| title_fullStr | Drosophila ubiquitin-specific peptidase 14 stabilizes the PERIOD protein by regulating a ubiquitin ligase SLIMB |
| title_full_unstemmed | Drosophila ubiquitin-specific peptidase 14 stabilizes the PERIOD protein by regulating a ubiquitin ligase SLIMB |
| title_short | Drosophila ubiquitin-specific peptidase 14 stabilizes the PERIOD protein by regulating a ubiquitin ligase SLIMB |
| title_sort | drosophila ubiquitin specific peptidase 14 stabilizes the period protein by regulating a ubiquitin ligase slimb |
| url | https://doi.org/10.1038/s42003-025-07632-9 |
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