The low molecular weight GTPase RhoA and atypical protein kinase Czeta are required for TLR2-mediated gene transcription.
The Rho GTPases are molecular switches that regulate many essential cellular processes, including actin dynamics, gene transcription, cell cycle progression, cell adhesion, and motility. In this study, we report that stimulation of TLR2 in human epithelial and monocytic cells leads to rapid and transient activation of RhoA. RhoA cooperated with the canonical I-kappaB kinase-mediated pathway that induces the release of NF-kappaB, in regulating the trans activation of the NF-kappaB subunit p65/RelA by affecting Ser(311) phosphorylation, and subsequent cytokine production. Another consequence of TLR2 stimulation by bacterial derived products was the activation of atypical protein kinase C (PKC) zeta and association of this protein kinase with RhoA. Inhibition of PKCzeta decreased NF-kappaB activation and p65/RelA trans activation without affecting I-kappaBalpha degradation. The observation of a transient, stimulus-dependent association of RhoA with PKCzeta suggests that RhoA mediates at least partially its effect on gene transcription through atypical PKC. In contrast to previous studies, identifying Rac1-PI3K as an upstream element in TLR2-initiated response to NF-kappaB, PI3K signaling was not required for RhoA or PKCzeta activity. These results indicate that multiple GTPase-regulated pathways emerge from stimulated Toll receptors, controlling different aspects of NF-kappaB-mediated gene transcription.
Teusch
Nicole
N
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Lombardo
Eleuterio
E
Eddleston
Jane
J
Knaus
Ulla G
UG
D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology*; D008970:Molecular Weight; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D014158:Transcription, Genetic; D020742:rhoA GTP-Binding Protein / Q000502:physiology*; D000099221:Protein Kinase C zeta
D008562:Membrane Glycoproteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D020742:rhoA GTP-Binding Protein; D000099221:Protein Kinase C zeta; C495342:TLR2 protein, human