Research ArticleCell Biology

Hereditary spastic paraplegia SPG8 mutations impair CAV1-dependent, integrin-mediated cell adhesion

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Science Signaling  07 Jan 2020:
Vol. 13, Issue 613, eaau7500
DOI: 10.1126/scisignal.aau7500

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Disease-associated mutations impair integrin recycling

Hereditary spastic paraplegia (HSP) type SPG8 is an inherited neurologic disorder associated with mutations in WASHC5, which encodes strumpellin, a component of the WASH complex, which localizes to endosomes and plays a role in endosomal sorting. Lee et al. found that strumpellin interacted with the caveolar protein CAV1 and inhibited its degradation. Cultured cells lacking strumpellin or expressing SPG8-associated strumpellin mutants exhibited impaired endosomal tubulation, reduced CAV1 at intracellular vesicles, and reduced integrin-mediated cell adhesion. The actin nucleation activity of the WASH complex was required for inhibiting the degradation of CAV1 and integrin α5, and the interaction between strumpellin and CAV1 was required for proper recycling of integrin α5 and for integrin-mediated cell adhesion. These findings suggest that the axon defects that characterize HSP type SPG8 may be due to disruption of strumpellin- and CAV1-dependent, integrin-mediated cell adhesion.

Abstract

Mutations in WASHC5 (also known as KIAA0196) cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG8. WASHC5, commonly called strumpellin, is a core component of the Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex that activates actin nucleation at endosomes. Although various other cellular roles for strumpellin have also been described, none account for how SPG8-associated mutations lead to HSP. Here, we identified protein interactors of the WASH complex by immunoprecipitation and mass spectrometry and assessed the functions of strumpellin in cultured cells using both overexpression and RNA interference along with cell-spreading assays to investigate cell adhesion. We uncovered a decrease in CAV1 protein abundance as well as endosomal fission defects resulting from pathogenic SPG8 mutations. CAV1, a key component of caveolae, interacted with strumpellin in cells, and strumpellin inhibited the lysosomal degradation of CAV1. SPG8-associated missense mutations in strumpellin did not rescue endosomal tubulation defects, reduction in CAV1 protein abundance, or integrin-mediated cell adhesion in strumpellin-deficient cells. Mechanistically, we demonstrated that the WASH complex maintained CAV1 and integrin protein amounts by inhibiting their lysosomal degradation through its endosomal actin nucleation activity. In addition, the interaction of strumpellin with CAV1 stimulated integrin recycling, thereby promoting cell adhesion. These findings provide a molecular link between WASHC5 mutations and impairment of CAV1- and integrin-mediated cell adhesion, providing insights into the cellular pathogenesis of SPG8.

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