Rip1 Mediates the Trif-dependent Toll-like Receptor 3- and 4-induced NF-κB Activation but Does Not Contribute to Interferon Regulatory Factor 3 Activation

Departments of Cancer Biology and Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2005; 280(44):36560-6. DOI: 10.1074/jbc.M506831200
Source: PubMed


Rip1 is required for IkappaB kinase activation in response to tumor necrosis factor alpha (TNF-alpha) and has been implicated in the Toll-like receptor 3 (TLR3) response to double-stranded RNA. Cytokine production is impaired when rip1-/- cells are treated with TNF-alpha, poly(I-C), or lipopolysaccharide, implicating Rip1 in the Trif-dependent TLR3 and TLR4 pathways. To examine the role of Rip1 in the Trif-dependent TLR4 pathway, we generated rip1-/- MyD88-/- cells. Lipopolysaccharide failed to stimulate NF-kappaB activation in rip1-/-MyD88-/- cells, revealing that Rip1 is also required for the Trif-dependent TLR4-induced NF-kappaB pathway. In addition to activating NF-kappaB, TLR3/4 pathways also stimulate interferon regulatory factor 3 activation. However, we find that Rip1 expression stimulates NF-kappaB but not interferon regulatory factor 3 activity. In the TNF-alpha pathway, Rip1 interacts with the E3 ubiquitin ligase Traf2 and is modified by polyubiquitin chains. Upon TLR3 activation, Rip1 is also modified by polyubiquitin chains and is recruited to TLR3 along with Traf6 and the ubiquitin-activated kinase Tak1. These studies suggest that Rip1 uses a similar, ubiquitin-dependent mechanism to activate IkappaB kinase-beta in response to TNF-alpha and TLR3 ligands.

1 Follower
14 Reads
  • Source
    • "TLR4 can also recruit TRIF in response to LPS, indirectly through interacting with another adaptor called TRAM (TRIFrelated adaptor molecule). Further studies have established that RIP1 acts as an essential adaptor in TLR3/4 induced NF-kB activation, which is dependent on TRIF [51] [52] (Fig. 3). Interestingly , TLR3/4 agonists could induce the polyubiquitination of RIP1, which is required for the subsequent IKK activation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Protein post-translational modifications (PTMs) are central to the host innate immune regulations. Dynamically, PTMs fine-tune the spatial and temporary responses of immune- and non-immune-cells, in accordance with extracellular and intracellular stresses. Ubiquitin and ubiquitin-like proteins (Ubls) are emerging as the important multi-functional signals, controlling the activation, stability, affinity and location of many signaling proteins. Recent investigations, at the molecular-cellular-animal models, have shed new light on the versatility of the ubiquitin, SUMO and ISG15, for shaping the strength and duration of the innate immune responses. This review summarizes our current knowledge on the functions and regulatory mechanisms of the ubiquitin and Ubls in the innate immunity, the first line of host defense against microbial infection.
    Cytokine & growth factor reviews 08/2013; 24(6). DOI:10.1016/j.cytogfr.2013.07.002 · 5.36 Impact Factor
  • Source
    • "This signaling branch appears to require CD14 for internalization of TLR4/MD-2/LPS into an endosomal compartment in which TRAM can interact with the TIR domain of TLR4 and recruit TRIF [28], [38], [39]. Signaling via the TRIF/TRAM branch does not recruit or activate IRAK but does recruit TRAF6 leading to TAK1 and RIP1 (receptor interacting protein 1) activation [40], [41]. This in turn activates MAPK and NF-κB, albeit with kinetics that is slightly delayed relative to those of the MyD88 pathway [25], [26]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Synthetic forms of E. coli monophosphoryl lipid A (sMLA) weakly activate the MyD88 (myeloid differentiation primary response protein) branch of the bifurcated TLR4 (Toll-like receptor 4) signaling pathway, in contrast to diphosphoryl lipid A (sDLA), which is a strong activator of both branches of TLR4. sMLA's weak MyD88 signaling activity is apparent downstream of TLR4/MyD88 signaling as we show that sMLA, unlike sDLA, is unable to efficiently recruit the TNF receptor-associated factor 6 (TRAF6) to the Interleukin-1 receptor-associated kinase 1 (IRAK1). This reduced recruitment of TRAF6 explains MLA's lower MAPK (Mitogen Activated Protein Kinase) and NF-κB activity. As further tests of sMLA's ability to activate TLR4/Myeloid differentiation factor 2 (MD-2), we used the antibody MTS510 as an indicator for TLR4/MD-2 heterotetramer formation. Staining patterns with this antibody indicated that sMLA does not effectively drive heterotetramerization of TLR4/MD-2 when compared to sDLA. However, a F126A mutant of MD-2, which allows lipid A binding but interferes with TLR4/MD-2 heterotetramerization, revealed that while sMLA is unable to efficiently form TLR4/MD-2 heterotetramers, it still needs heterotetramer formation for the full extent of signaling it is able to achieve. Monophosphoryl lipid A's weak ability to form TLR4/MD-2 heterotetramers was not restricted to synthetic E. coli type because cells exposed to a biological preparation of S. minnesota monophosphoryl lipid A (MPLA) also showed reduced TLR4/MD-2 heterotetramer formation. The low potency with which sMLA and MPLA drive heterotetramerization of TLR4/MD-2 contributes to their weak MyD88 signaling activities.
    PLoS ONE 04/2013; 8(4):e62622. DOI:10.1371/journal.pone.0062622 · 3.23 Impact Factor
  • Source
    • "Then NFÄB nuclear localization sequence is unmasked by degradation effect of phosphorylated IKB. Activation of NFÄB and transcriptional induction of target genes requires signalling from TRIF via RIP1 (Cusson-Hermance et al., 2005). NFÄB up regulation via TRIF, TRAF 6 results in up regulation of IL-10 which leads to expression of SOCS via JAK/STAT pathway (Patil et al., 2010; Kinjyo et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hybrid automata models have been used in literature to represent the behavior of excitable cells, in particular their characteristic action potential. One of these models [14] describes the action potential of neurons, which belong to the class of excitable cells. However, this model does not take the sensitivity of a synapse to presynaptic action potentials into account, an effect also known as synaptic plasticity. Hebb's learning postulate describes the sensitivity of a synapse in firing the postsynaptic spikes. In this paper, we extend the existing neuron action potential hybrid automata model to incorporate Hebb's learning postulate. We propose a class of Parametric Linear Hybrid Automata as a suitable modeling formalism for the extended model. We analyze the model using the PHAVer model checker that support parametric analysis as well as the composition of automata.
    First International Symposium on Computational Sciences; 06/2012
Show more


14 Reads
Available from