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TGFβ-Induced Phosphorylation of Usp9X Stabilizes Ankyrin-G and Regulates Dendritic Spine Maintenance

31 Pages Posted: 10 Jan 2020 Sneak Peek Status: Review Complete

See all articles by Sehyoun Yoon

Sehyoun Yoon

Northwestern University - Department of Physiology

Euan Parnell

Northwestern University - Department of Physiology

Peter Penzes

Northwestern University - Department of Physiology

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Abstract

Signaling by the cytokine TGFβ has been implicated in a multitude of biological functions outside and within the nervous system. While canonical TGFβ signaling is mediated by Smad-dependent regulation of gene expression, non-canonical TGFβ signaling, in particular in the central nervous system, remains largely unexplored. ANK3 variants (encoding ankyrin-G) are associated with bipolar disorder, intellectual disability, and autism spectrum disorder, while mutations in USP9X, which encodes a deubiquitinase, are associated with X-linked intellectual disability and autism in humans. Here we show that TGFβ signaling promotes Usp9X phosphorylation, which enhances its interaction with ankyrin-G, and stabilizes ankyrin-G in spines, leading to spine enlargement. Using in situ proximity ligation combined with structured illumination super-resolution microscopy we characterize the postsynaptic spatial organization of phosphorylation-dependent regulation of Usp9X/ankyrin-G interaction in dendrites and its quantitative relationship with spine morphology and number. These data reveal a cytokine-mediated mechanism regulating protein stability in spines, and suggest a role for deubiquitination and TGFβ signaling in neurodevelopmental disorder pathogenesis and treatment.

Keywords: deubiquitinase, TGFβ, proximity ligation assay, structured illumination microscopy, ankyrin-G, Usp9X

Suggested Citation

Yoon, Sehyoun and Parnell, Euan and Penzes, Peter, TGFβ-Induced Phosphorylation of Usp9X Stabilizes Ankyrin-G and Regulates Dendritic Spine Maintenance. CELL-REPORTS-D-19-05040. Available at SSRN: https://ssrn.com/abstract=3516896 or http://dx.doi.org/10.2139/ssrn.3516896
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Sehyoun Yoon

Northwestern University - Department of Physiology

2001 Sheridan Road
Evanston, IL 60208
United States

Euan Parnell

Northwestern University - Department of Physiology

2001 Sheridan Road
Evanston, IL 60208
United States

Peter Penzes (Contact Author)

Northwestern University - Department of Physiology ( email )

2001 Sheridan Road
Evanston, IL 60208
United States

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