Activation of the small GTPase Cdc42 by the inflammatory cytokines TNFα and IL-1, and by the Epstein-Barr virus transforming protein LMP1

Abstract

Cdc42, a Rho-family GTPase, has been implicated in several signal transduction pathways, including organization of the actin cytoskeleton, activation of the c-Jun N-terminal MAP kinase (JNK) and stimulation of the nuclear transcription factor kappa B (NF(kappa)B). We report here that exposure of fibroblasts to the inflammatory cytokines tumor necrosis factor (alpha) (TNF(alpha)) and interleukin-1 (IL-1) triggers the activation of Cdc42 leading first to filopodia formation and subsequently to Rac and Rho activation. Inhibition of Cdc42 completely suppresses cytokine-induced actin polymerization, but not activation of JNK or NF(kappa)B. The latent membrane protein 1 of Epstein-Barr virus, LMP1, is thought to mimic constitutively activated TNF family receptors. When expressed in fibroblasts, LMP1 stimulates Cdc42-dependent filopodia formation as well as JNK and NF(kappa)B activation. Using LMP1 mutants, we show that activation of Cdc42 and JNK/NF(kappa)B occur through distinct pathways and that Cdc42 activation is independent of LMP1's interaction with TRADD and TRAF proteins.

Extracellular vesicles derived from ODN-stimulated macrophages transfer and activate Cdc42 in recipient cells and thereby increase cellular permissiveness to EV uptake

“…The activation of Cdc42 by TNF- has been implicated in the regulation of endocytosis and induction of actin polymerization (32,33). Filopodia formation has been proven to be an effective means to monitor the activation of Cdc42 (32,33). We showed that TNF- induced the formation of filopodia in RAW 264.7 cells (Fig.…”

“…To gain further mechanistic insights, we used FITC-phalloidin to stain actin and examined its morphology to evaluate the activation of Cdc42. The activation of Cdc42 by TNF- has been implicated in the regulation of endocytosis and induction of actin polymerization (32,33). Filopodia formation has been proven to be an effective means to monitor the activation of Cdc42 (32,33).…”

SARS-CoV-2 infected cells sprout actin-rich filopodia that facilitate viral invasion

“…From the biochemical perspective, Ras-related superfamily of small GTPases can trigger the formation of actin-based structures (Nobes and Hall 1995, Tapon and Hall 1997, Hall 1998). Correspondingly, numbers of viruses can control over the formation of actin-rich filopodia through modulating Rac, Rho, Cdc42, which in turn enhance virus uptake (Ohta et al 1999, Puls et al 1999, Smith et al 2008, Zamudio-Meza et al 2009, Nikolic et al 2011, Taylor et al 2011, Xiang et al 2012, Freeman et al 2014, Chang et al 2022, Hunziker et al 2022). Recent study reported that SARS-CoV-2 infection induces the upregulation of actin cytoskeleton via the kinase effectors of Rho GTPases (Liu et al 2020).…”

Cytoplasmic and Nuclear Functions of cIAP1

“…Cell shape and cell motility are controlled by small GTPases of the Rho family. These proteins are critical regulators of the dynamic reorganization of the actin cytoskeleton [ 101 , 102 , 103 ]. They control cell architecture, focal adhesion complexes and local contraction by promoting the generation of stress fibers or membrane protrusions such as lamellopodia or filopodia [ 104 ].…”

“…Accordingly, cIAP1 −/− fibroblasts display an enhanced ability to migrate and exhibit filopodia. TNFα has the ability to induce cdc42 activation and actin reorganisation [ 102 , 103 ]. Upon TNFα stimulation, cIAP1 is recruited to the membrane receptor-associated complex, releasing cdc42 and promoting its activation [ 106 ] ( Figure 4 ).…”