Dia2 formin controls receptor activity by organizing plasma membrane lipid partitioning at the nanoscale

Abstract

Activation of JAK/STAT signaling by IFN-{gamma} requires partitioning of IFN-{gamma}R into specific lipid nanodomains at the plasma membrane. Using IFN-{gamma}R as a proxy, we investigated the role of actin dynamics in the formation and organization of lipid nanodomains, a process that remains poorly understood. We identified formin Dia2/DIAPH3 as a specific and RhoA -dependent regulator of IFN-{gamma}-induced JAK/STAT signaling. Based on lipidomics and specific probes enabling membrane lipid imaging by super resolution microscopy, we demonstrate that Dia2 is required for proper assembly of sphingomyelin and cholesterol lipid complexes. Finally, we show that the disorganization of lipid nanodomains induced by Dia2 depletion results in drastic changes in nano-partitioning and activity of other membrane proteins, such as Thy1 and PD-L1. Our data establish, therefore, the central role of the RhoA-Dia2 axis in the regulation of IFN-{gamma} induced JAK/STAT signaling, and more broadly, in the nanoscale organization of the plasma membrane.