CYRI-A limits invasive migration through macropinosome formation and integrin uptake regulation.

Anh Hoang Le,Savvas Nikolaou,Shehab Ismail,Laura M Machesky,Tamas Yelland,Nikki R Paul,Loic Fort

doi:10.1083/jcb.202012114

Abstract

The Scar/WAVE complex drives actin nucleation during cell migration. Interestingly, the same complex is important in forming membrane ruffles during macropinocytosis, a process mediating nutrient uptake and membrane receptor trafficking. Mammalian CYRI-B is a recently described negative regulator of the Scar/WAVE complex by RAC1 sequestration, but its other paralogue, CYRI-A, has not been characterized. Here, we implicate CYRI-A as a key regulator of macropinosome formation and integrin internalization. We find that CYRI-A is transiently recruited to nascent macropinosomes, dependent on PI3K and RAC1 activity. CYRI-A recruitment precedes RAB5A recruitment but follows sharply after RAC1 and actin signaling, consistent with it being a local inhibitor of actin polymerization. Depletion of both CYRI-A and -B results in enhanced surface expression of the α5β1 integrin via reduced internalization. CYRI depletion enhanced migration, invasion, and anchorage-independent growth in 3D. Thus, CYRI-A is a dynamic regulator of macropinocytosis, functioning together with CYRI-B to regulate integrin trafficking.

Highlights

The actin cytoskeleton is a multifaceted network coordinating essential cellular processes such as cell migration and endocytosis
CYFIP-related RAC1 interacting (CYRI) proteins bind to RAC1 and oppose recruitment and activation of Scar/WAVE complex in lamellipodia (Fort et al, 2018)
Fort et al (2018) showed that CYRI-B can decrease RAC1 activation in cells by an unknown mechanism and likely sequester RAC1 away from interaction with Scar/WAVE or somehow disrupt RAC1 signaling to Scar/WAVE (Fort et al, 2018)

Summary

Introduction

The actin cytoskeleton is a multifaceted network coordinating essential cellular processes such as cell migration and endocytosis. RAC1-induced actin polymerization contributes to endocytic processes (Mooren et al, 2012; Egami et al, 2014; Bloomfield and Kay, 2016; Ferreira and Boucrot, 2018; Hinze and Boucrot, 2018). The branched actin network underpins membrane ruffling, a prerequisite for macropinocytosis, an ancient endocytic pathway for uptake of external substances, or to counteract cytoplasmic hydrostatic pressure to drive membrane curvature and invagination (Carlsson, 2018). Following RAC1 activation, RAC1 inactivation is required for the completion of macropinocytosis (Yoshida et al, 2009; Fujii et al, 2013). Activating RAC1 by photoactivation led to unresolved membrane invagination (Fujii et al, 2013). The related process phagocytosis has been shown to require several

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Conclusion