Rip1 Mediates the Trif-dependent Toll-like Receptor 3- and 4-induced NF- B 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.

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    • "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. "
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    • "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]. "
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    • "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). "
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