T cell receptor‐induced lipid raft recruitment of the IκB kinase complex is necessary and sufficient for NF‐κB activation occurring in the cytosol

Sebald, Andrea; Mattioli, Ivan; Schmitz, M. Lienhard

doi:10.1002/eji.200425024

Cited by 20 publications

(21 citation statements)

References 49 publications

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“…Increased uptake of E. coli could also be contributed by the facilitated association of membrane lipid rafts with CD14, which promotes infection by Gram-negative bacteria (40). Moreover, recruitment of IκB kinase into lipid raft clusters could not only support internalization but also incite cytokine expression through activation of NFκB (41). Wnt5a-Fz5-mediated high internalization rates of E. coli/latex beads are likely to make room for additional binding of the same, thus causing amplification of signaling.…”

Section: Discussionmentioning

confidence: 94%

The Wingless homolog Wnt5a stimulates phagocytosis but not bacterial killing

Maiti

Naskar

Sen

2012

Proc. Natl. Acad. Sci. U.S.A.

110

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Phagocytosis is a primary defense program orchestrated by monocytes/macrophages. Unregulated phagocytosis can lead to pathological conditions. In the current study we have demonstrated that Wnt5a stimulates phagocytosis through PI3 kinase-Rac1 and lipid-raft-dependent processes. Wnt5a-mediated augmentation in phagocytosis is suppressed by blocking expression of the putative Wnt5a receptor Frizzled 5. Enhanced phagocytosis of bacteria by Wnt5a-Fz5 signaling increases the secretion of proinflammatory cytokines, but not the bacterial killing rate. Furthermore, a small molecule inhibitor of Wnt production, IWP-2, which reduces secretion of functionally active Wnt5a, not only suppresses both phagocytosis and the secretion of proinflammatory cytokines but also accelerates the bacterial killing rate.

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Section: Discussionmentioning

confidence: 94%

The Wingless homolog Wnt5a stimulates phagocytosis but not bacterial killing

Maiti

Naskar

Sen

2012

Proc. Natl. Acad. Sci. U.S.A.

110

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“…Western blots were serially probed to detect Myc-tagged CARMA1, IKKg MALT1/Traf/Ubiquitin complex with IKKg. Similarly, while targeting of NEMO to T cell rafts leads to a basal increase in NF-kB signaling (Sebald et al, 2005;Weil et al, 2003), this signal remains PKC inducible and is blocked by PKC inhibition. We suggest that PKC-activated CARMA1 functions in this latter system to efficiently colocalize its downstream effectors.…”

Section: Discussionmentioning

confidence: 97%

Phosphorylation of the CARMA1 Linker Controls NF-κB Activation

et al. 2005

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PKC isoforms and CARMA1 play crucial roles in immunoreceptor-dependent NF-kappaB activation. We tested whether PKC-dependent phosphorylation of CARMA1 directly regulates this signaling cascade. B cell antigen receptor (BCR) engagement led to the progressive recruitment of CARMA1 into lipid rafts and to the association of CARMA1 with, and phosphorylation by, PKCbeta. Furthermore, PKCbeta interacted with the serine-rich CARMA1 linker, and both PKCbeta and PKCtheta phosphorylated identical serine residues (S564, S649, and S657) within this linker. Mutation of two of these sites ablated the functional activity of CARMA1. In contrast, deletion of the linker resulted in constitutive, receptor- and PKC-independent NF-kappaB activation. Together, our data support a model whereby CARMA1 phosphorylation controls NF-kappaB activation by triggering a shift from an inactive to an active CARMA1 conformer. This PKC-dependent switch regulates accessibility of the CARD and CC domains and controls assembly and full activation of the membrane-associated IkappaB kinase (IKK) signalosome.

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“…Moreover, MALT1 contains two putative TRAF6 binding sites that, when mutated, lead to a decrease in MALT1-mediated IKK activation (45). TRAF2/6, MALT1, and IKK members migrate to lipid rafts following TCR stimulation, and expression of raft-targeted IKK␥ is sufficient to directly drive IB␣ phosphorylation and NF-B signaling (49). The active caspase complex we describe resides exclusively in lipid rafts and contains many of the components necessary for TCR-mediated NF-B signaling.…”

Section: Discussionmentioning

confidence: 99%

Caspase-8 and c-FLIPL Associate in Lipid Rafts with NF-κB Adaptors during T Cell Activation

Misra

Russell

Koenig

et al. 2007

Journal of Biological Chemistry

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Humans and mice lacking functional caspase-8 in T cells manifest a profound immunodeficiency syndrome due to defective T cell antigen receptor (TCR)-induced NF-B signaling and proliferation. It is unknown how caspase-8 is activated following T cell stimulation, and what is the caspase-8 substrate(s) that isActivation of caspases has traditionally been associated with oligomerization of death receptors and induction of cell death (1). It has been determined more recently that caspase activity is also required for the induction of proliferation by primary naïve human and murine T cells (2-4). Inhibition of caspase activity by the pan-caspase blocker, Z-VAD-fmk, 4 or the caspase-8-specific blocker, IETD-fmk, greatly reduced production of IL-2 and proliferation following TCR ligation (2, 3). It was subsequently shown that a non-functional mutation in the caspase-8 gene in humans (5, 6) or the deletion of caspase-8 in murine T cells (7) resulted in an immunodeficiency syndrome characterized by markedly decreased production of IL-2 and proliferative capacity of T cells. It remained uncertain from these studies how caspase activation was linked to T cell antigen receptor (TCR) ligation, what were the regulatory protein(s) and substrate(s) of caspase activity, and whether this required the presence of the death receptor Fas (CD95/APO1). Equally puzzling was how the activation of caspase-8 might be limited to avoid induction of apoptosis. We recently observed that following T cell activation, cleavage occurs of certain known caspase substrates, such as c-FLIP-Long form (c-FLIP L ) and RIP1, although another caspase-8 substrate associated with cell death, Bid, was not cleaved (4). This suggested that active caspase-8 may become sequestered in a specific site within T cells after activation.We considered the possibility of c-FLIP L as both an activator of caspase-8 and an early caspase-8 substrate after T cell activation. c-FLIP L is homologous to caspase-8 in containing two death effector domains, but bears a mutation in the caspase domain, which renders it enzymatically inactive (8). Following ligation of Fas, c-FLIP L is co-recruited with caspase-8 to the death-inducing signal complex (1,8). In addition, c-FLIP L is able to directly heterodimerize with and activate caspase-8 in its full-length form, independently of Fas (9 -11). c-FLIP L , furthermore, contains a caspase cleavage site at Asp 376 that yields processed p43 FLIP (12, 13). As such, c-FLIP L may be an early caspase-8 substrate during T cell activation. c-FLIP L also associates with RIP1 and TRAF2 to promote activation of NF-B (14). Mice overexpressing c-FLIP L in the T cell compartment manifest augmented IL-2, and enhanced proliferation (15, 16). Collectively, c-FLIP L may provide an important link in our understanding of how TCR stimulation activates caspase-8, what is the caspase-8 substrate(s), and how caspase activity may link to NF-B activation.

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T cell receptor‐induced lipid raft recruitment of the IκB kinase complex is necessary and sufficient for NF‐κB activation occurring in the cytosol

Cited by 20 publications

References 49 publications

The Wingless homolog Wnt5a stimulates phagocytosis but not bacterial killing

The Wingless homolog Wnt5a stimulates phagocytosis but not bacterial killing

Phosphorylation of the CARMA1 Linker Controls NF-κB Activation

Caspase-8 and c-FLIPL Associate in Lipid Rafts with NF-κB Adaptors during T Cell Activation

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