A Role for Mammalian Diaphanous-Related Formins in Complement Receptor (CR3)-Mediated Phagocytosis in Macrophages

Abstract

Macrophages, dendritic cells, and neutrophils use phagocytosis to capture and clear off invading pathogens. The process is triggered by the interaction of ligands on the pathogens' surface with specific phagocytic receptors, including immunoglobulin (FcR) and complement C3bi (CR3) receptors (integrin alpha(M)beta2, Mac1) . Localized actin-filament assembly that acts as the driving force for particle engulfment is controlled by Rho-family small GTPases . RhoA regulates CR3-mediated phagocytosis through a mechanism that is still unclear . Mammalian Diaphanous-related (mDia) formins participate in the generation of a diverse set of actin-remodeling events downstream of RhoA , and mDia1 is recruited around fibronectin-coated beads in a RhoA-dependent manner in fibroblasts . Here, we set out to examine whether mDia proteins are involved in CR3-mediated phagocytosis in macrophages. We show that the RhoA effector mDia1 is recruited early during CR3-mediated phagocytosis and colocalizes with polymerized actin in the phagocytic cup. Interfering with mDia activity inhibits CR3-mediated phagocytosis while having no effect on FcR-mediated phagocytosis. These results indicate a new function for mDia proteins in the regulation of actin polymerization during CR3-mediated phagocytosis.

Initiation of lamellipodia and ruffles involves cooperation between mDia1 and the Arp2/3 complex

“…Consistent with being activated by Rho, mDia1 also acts as a Rho effector, regulating actin-dependent processes (Chesarone et al, 2010;Kim et al, 2009). mDia1 is a component of the phagocytosis cup (Brandt et al, 2007;Colucci-Guyon et al, 2005;Lewkowicz et al, 2008) and might also localize at the leading edge of migrating cells and within ruffles (Kurokawa and Matsuda, 2005;Watanabe et al, 1997;Zaoui et al, 2008).…”

RhoA determines disease progression by controlling neutrophil motility and restricting hyperresponsiveness

“…11,12 Further, RhoA-mDia signaling has been implicated in CR3-and Fcg-mediated phagocytosis. [13][14][15] remains limited. 7,10 To better understand how disruption of Rho signaling will alter neutrophil biology, mice with myeloid lineagespecific RhoA and combined RhoA/RhoB deletion were generated.…”

The Formins FMNL1 and mDia1 Regulate Coiling Phagocytosis of Borrelia burgdorferi by Primary Human Macrophages

“…Formins are multidomain proteins that can be autoinhibited by an intramolecular interaction between their DID and Cterminal DAD domains (34), with the latter also playing a role in actin nucleation (35). From 15 formins expressed in mammalian cells, 3 have so far been implicated in phagocytic processes: mDia1, mDia2 (36), and FMNL1 (37).…”