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Remodeling without destruction: non-proteolytic ubiquitin chains in neural function and brain disorders

Molecular Psychiatry volume 26, pages 247–264 (2021)Cite this article

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Abstract

Ubiquitination is a fundamental posttranslational protein modification that regulates diverse biological processes, including those in the CNS. Several topologically and functionally distinct polyubiquitin chains can be assembled on protein substrates, modifying their fates. The classical and most prevalent polyubiquitin chains are those that tag a substrate to the proteasome for degradation, which has been established as a major mechanism driving neural circuit deconstruction and remodeling. In contrast, proteasome-independent non-proteolytic polyubiquitin chains regulate protein scaffolding, signaling complex formation, and kinase activation, and play essential roles in an array of signal transduction processes. Despite being a cornerstone in immune signaling and abundant in the mammalian brain, these non-proteolytic chains are underappreciated in neurons and synapses in the brain. Emerging studies have begun to generate exciting insights about some fundamental roles played by these non-degradative chains in neuronal function and plasticity. In addition, their roles in a number of brain diseases are being recognized. In this article, we discuss recent advances on these nonconventional ubiquitin chains in neural development, function, plasticity, and related pathologies.

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Fig. 1: Different faces of polyubiquitin linkages.
Fig. 2: Roles of non-proteolytic polyUb in signalosome formation, kinase activation, and genome integrity.
Fig. 3: Non-proteolytic ubiquitination in synapse development and remodeling.
Fig. 4: Non-proteolytic ubiquitination regulates Hebbian synaptic plasticity.
Fig. 5: Non-proteolytic ubiquitination regulates homeostatic plasticity.

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Acknowledgements

We thank members of the laboratory for comments and discussions. This study was supported by NIH grants MH106489 and NS093097 (W-DY).

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    Alexis Zajicek & Wei-Dong Yao

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Zajicek, A., Yao, WD. Remodeling without destruction: non-proteolytic ubiquitin chains in neural function and brain disorders. Mol Psychiatry 26, 247–264 (2021). https://doi.org/10.1038/s41380-020-0849-7

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