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Abstract

The functions of integrins are tightly regulated via multiple mechanisms including trafficking and degradation. Integrins are repeatedly internalized, routed into the endosomal system and either degraded by the lysosome or recycled back to the plasma membrane. The ubiquitin system dictates whether internalized proteins are degraded or recycled. Here, we use a genetic screen and proximity-dependent biotin identification to identify deubiquitinase(s) that control integrin surface levels. We find that a ternary deubiquitinating complex, comprised of USP12 (or the homologous USP46), WDR48 and WDR20, stabilizes beta 1 integrin (Itgb1) by preventing ESCRT-mediated lysosomal degradation. Mechanistically, the USP12/46-WDR48-WDR20 complex removes ubiquitin from the cytoplasmic tail of internalized Itgb1 in early endosomes, which in turn prevents ESCRT-mediated sorting and Itgb1 degradation.
A deubiquitinase complex consisting of USP12/46-WDR48-WDR20 deubiquitinates the cytoplasmic domains of integrins and numerous additional cell surface proteins at early endosomes, which prevents their ESCRT-mediated lysosomal degradation and promotes their recycling back to the cell surface.The ternary USP12/46-WDR48-WDR20 complex maintains Itgb1 surface levels.USP12/46-WDR48-WDR20-mediated deubiquitination of Itgb1 inhibits ESCRT-mediated degradation.Expression of USP12/46-WDR48-WDR20 correlates with Itgb1 stability, cell adhesion, migration and invasion.
A deubiquitinase complex consisting of USP12/46-WDR48-WDR20 deubiquitinates the cytoplasmic domains of integrins and numerous additional cell surface proteins at early endosomes, which prevents their ESCRT-mediated lysosomal degradation and promotes their recycling back to the cell surface.