Formins as effector proteins of Rho GTPases

Abstract

Formin proteins were recognized as effectors of Rho GTPases some 15 years ago. They contribute to different cellular actin cytoskeleton structures by their ability to polymerize straight actin filaments at the barbed end. While not all formins necessarily interact with Rho GTPases, a subgroup of mammalian formins, termed Diaphanous-related formins or DRFs, were shown to be activated by small GTPases of the Rho superfamily. DRFs are autoinhibited in the resting state by an N- to C-terminal interaction that renders the central actin polymerization domain inactive. Upon the interaction with a GTP-bound Rho, Rac, or Cdc42 GTPase, the C-terminal autoregulation domain is displaced from its N-terminal recognition site and the formin becomes active to polymerize actin filaments. In this review we discuss the current knowledge on the structure, activation, and function of formin-GTPase interactions for the mammalian formin families Dia, Daam, FMNL, and FHOD. We describe both direct and indirect interactions of formins with GTPases, which lead to formin activation and cytoskeletal rearrangements. The multifaceted function of formins as effector proteins of Rho GTPases thus reflects the diversity of the actin cytoskeleton in cells.

Deoxyhypusine Modification of Eukaryotic Translation Initiation Factor 5A (eIF5A) Is Essential for Trypanosoma brucei Growth and for Expression of Polyprolyl-containing Proteins

“…A number of the proteins with long poly-(Pro) tracts including for example formin, flagellum adhesion glycoprotein, and calpain were shown in a genome-wide RNAi screen to be required for fitness in T. brucei (44); thus the loss of eIF5A is expected to lead to the depletion of many essential proteins in the parasite and to have a pleomorphic effect on multiple cell processes. Interestingly many of the proteins in T. brucei with long poly-(Pro) tracts are involved in regulation of the actin cytoskeleton, the remodeling of which is essential for diverse cellular processes including cytokinesis, endosome trafficking, cell polarization, and motility (47). The role of eIF5A in promoting translation of actin regulatory proteins correlates with our observation that knockdown of TbeIF5A led to abnormal cell morphologies in both BSF and PF parasites.…”

“…The role of eIF5A in promoting translation of actin regulatory proteins correlates with our observation that knockdown of TbeIF5A led to abnormal cell morphologies in both BSF and PF parasites. Formin and CAP/ Srv2p, which we have shown are depleted after eIF5A knockdown, are both involved in the regulation of actin filament assembly (47,48). Depletion of eIF5A in S. cerevisiae also resulted in misshapen cells that were more sensitive to ethanol (49).…”

Cytoskeletal control of B cell responses to antigens

“…RHOA is important for B cell development and survival 73 and stimulates a key formin, DIAP1. The importance of formin-mediated actin polymerization in B cells is largely unexplored, but studies in T cells suggest that DIAP1 and FMNL1, a formin activated by RAC and CDC42 74 , are important for multiple aspects of immune synapse formation including adhesion, formation of contractile rings and polarization of microtubules [75][76][77] .…”

IRAP+ endosomes restrict TLR9 activation and signaling

“…Actin polymerization around the endosomal vesicles containing TLR9 ligands has been shown to be also driven by the other key actin nucleation factor, Arp2/3, and to be essential in limiting TLR9 signaling 37 . Both, FHOD4 and Arp2/3 are activated by the same small GTPase of Rho family, Cdc42 35 , suggesting that these two actin-remodeling factors might cooperate in the regulation of TLR9 signaling, like they cooperate in phagocytic cup formation 38 .…”

“…Formins are major actin nucleation factors that drive the assembly of actin monomers into filamentous structures and remain associated with the barbed end during filament elongation 35 . A knock-down of FHOD4 had effects similar to IRAP deletion on TLR9 trafficking and the cellular response to CpG.…”