Proximity interactome mapping furthers a role for spinophilin in protein homeostasis.

Nov 10, 2025iScience

New Insights into Spinophilin's Role in Protein Balance

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Abstract

Spinophilin is a protein found in brain cells that helps organize other proteins and is involved in controlling their activity. In this study, we developed a new method to identify the proteins that interact with spinophilin. We discovered over 600 proteins that work with spinophilin, many of which are important for processing genetic information. Additionally, we found that spinophilin may help balance its own levels while encouraging the production of other important proteins in the brain. Our findings suggest that spinophilin plays a key role in how proteins are made and managed in brain cells.

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Spinophilin is a dendritic spine-enriched scaffolding and protein phosphatase 1-targeting protein. To detail spinophilin-interacting proteins, we created an UltraID and ALFA-tagged spinophilin-encoding construct that permits proximity labeling and orthogonal nanobody pull-down (ID-oPD) of spinophilin-associated protein complexes in heterologous cells. Using this ID-oPD approach, we identified 614 UltraID-specific and 312 UltraID-specific and spinophilin-selective spinophilin-interacting proteins in HEK293 cells and validated a subset of these using orthogonal approaches. Many of these proteins are involved in mRNA processing and translation. In the brain, we determined that spinophilin mRNA is highly neuropil localized and that spinophilin may normally function to limit its own expression but promote the expression of other postsynaptic density (PSD)-associated proteins. Overall, our use of an ID-oPD approach uncovers a putative role for spinophilin in mRNA translation and PSD protein expression.

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Abstract

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