Abstract
An open question in neuroscience is how protein posttranslational modifications regulate synaptic site targeting. Polyubiquitination plays a role in proteasome-mediated protein turnover; however, additional functions for specific types of polyubiquitin linkages have been identified. One type of polyubiquitination, K63-polyubiquitin (K63-polyUb), has been studied for its role in signal transduction within the context of cancer, but little has been done to uncover its role regarding neuronal and synaptic function. Here, we report an emerging function for the cytosolic PSD-95 interactor, cypin, in the regulation of synaptic content by K63-polyUb during neuronal development in vitro and in adult mice in vivo. We identify cypin-promoted K63-polyUb on postsynaptic proteins and also find an important role for cypin in presynaptic function. Our work demonstrates that cypin-promoted changes to K63-polyUb can regulate synaptic content and function on both sides of the synapse, adding important insight into basic mechanisms of neuronal signaling.
| Original language | English |
|---|---|
| Article number | eads5467 |
| Journal | Science advances |
| Volume | 11 |
| Issue number | 28 |
| DOIs | |
| State | Published - Jul 11 2025 |
Bibliographical note
Publisher Copyright:Copyright © 2025 The Authors, some rights reserved;
Funding
Acknowledgments: We thank h. Zheng for help with analysis of in vitro proteomic data and F. tescarollo for help with two-way AnOvA analysis. Mass spectrometry analysis was performed by the integrated Mass Spectrometry Unit at Michigan State University for samples from in vivo studies and the Biological Mass Spectrometry Facility of Robert Wood Johnson Medical School and Rutgers, the State University of new Jersey for in vitro studies. Funding: this work was supported by the new Jersey commission on Brain injury Research grant cBiR20iRG003 (B.l.F.), the national institute of neurological disorders and Stroke grants 1R56nS135406-01 and 1R01nS135406-01A1 (B.l.F.), the new Jersey commission on Brain injury Research predoctoral fellowship cBiR20Fel009 (S.R.G.), the new Jersey commission on Brain injury Research postdoctoral fellowship cBiR24Fel013 (S.R.G.), the new Jersey commission on Brain injury Research predoctoral fellowship cBiR15Fel009 (M.v.P.), and the Rutgers University Busch Biomedical Research Grant (K.M.). Author contributions: S.R.G.: Writing—original draft, investigation, writing—review and editing, methodology, data curation, validation, formal analysis, and visualization. A.R.R.: investigation and methodology. J.l.: Writing—original draft, investigation, writing—review and editing, methodology, data curation, validation, and formal analysis. M.v.P.: Writing—review and editing, investigation, and visualization. K.M.: Writing— original draft, writing—review and editing, and methodology. i.e.v.: Writing—original draft, conceptualization, writing—review and editing, methodology, resources, and supervision. B.l.F.: Writing—original draft, conceptualization, writing—review and editing, funding acquisition, supervision, and project administration. Competing interests: the authors declare that they have no competing interests Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. data and accompanying analyses have been deposited to dryad (https://doi. org/10.5061/dryad.sbcc2frjh). the mass spectrometry proteomic data have been deposited to the ProteomeXchange consortium (http://proteomecentral.proteomexchange.org) via the PRide (97) partner repository with the dataset identifier PXd055383 and 10.6019/PXd055383. We thank H. Zheng for help with analysis of in vitro proteomic data and F. Tescarollo for help with two-way ANOVA analysis. Mass spectrometry analysis was performed by The Integrated Mass Spectrometry Unit at Michigan State University for samples from in vivo studies and the Biological Mass Spectrometry Facility of Robert Wood Johnson Medical School and Rutgers, The State University of New Jersey for in vitro studies. This work was supported by the New Jersey Commission on Brain Injury Research grant CBIR20IRG003 (B.L.F.), the National Institute of Neurological Disorders and Stroke grants 1R56NS135406-01 and 1R01NS135406-01A1 (B.L.F.), the New Jersey Commission on Brain Injury Research predoctoral fellowship CBIR20FEL009 (S.R.G.), the New Jersey Commission on Brain Injury Research postdoctoral fellowship CBIR24FEL013 (S.R.G.), the New Jersey Commission on Brain Injury Research predoctoral fellowship CBIR15FEL009 (M.V.P.), and the Rutgers University Busch Biomedical Research Grant (K.M.).
| Funders | Funder number |
|---|---|
| New Jersey Racing Commission | |
| Michigan State University | |
| new Jersey commission on Brain | |
| Integrated Mass Spectrometry Unit | |
| Rutgers University Busch Biomedical Research | |
| Biological Mass Spectrometry Facility of Robert Wood Johnson Medical School | |
| National Institute of Neurological Disorders and Stroke | 1R56nS135406-01, 1R01NS135406-01A1, CBIR20FEL009, CBIR24FEL013, CBIR15FEL009 |
| The State University of New Jersey | CBIR20IRG003 |
UN SDGs
This output contributes to the following UN Sustainable Development Goals (SDGs)
-
SDG 3 Good Health and Well-being
ASJC Scopus subject areas
- General
Fingerprint
Dive into the research topics of 'Cypin regulates K63-linked polyubiquitination to shape synaptic content'. Together they form a unique fingerprint.Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver