A Novel, Retromer-Independent Role for Sorting Nexins 1 and 2 in RhoG-Dependent Membrane Remodeling

The sorting nexins SNX1 and SNX2 are members of the retromer complex involved in protein sorting within the endocytic pathway. While retromer-dependent functions of SNX1 and SNX2 have been well documented, potential retromer-independent roles remain unclear. Here, we show that SNX1 and SNX2 interact with the Rac1 and RhoG guanine nucleotide exchange factor Kalirin-7. Simultaneous overexpression of SNX1 or SNX2 and Kalirin-7 in epithelial cells causes partial redistribution of both SNX isoforms to the plasma membrane, and results in RhoG-dependent lamellipodia formation that requires functional Phox homology (PX) and Bin/Amphiphysin/Rvs (BAR) domains of SNX, but is Rac1- and retromer-independent. Conversely, depletion of endogenous SNX1 or SNX2 inhibits Kalirin-7-mediated lamellipodia formation. Finally, we demonstrate that SNX1 and SNX2 interact directly with inactive RhoG, suggesting a novel role for these SNX proteins in recruiting an inactive Rho GTPase to its exchange factor.