Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses

Fukushima, Toru; Matsuzawa, Shu‐ichi; Kress, Christina L.; Bruey, Jean Marie; Krajewska, Maryla; Lefebvre, Sophie; Zapata, Juán M.; Ronai, Ze’ev A.; Reed, John C.

doi:10.1073/pnas.0700548104

Cited by 104 publications

(106 citation statements)

References 33 publications

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“…In response to TNF-a, UBC13 þ /À macrophages and splenocytes showed blunted activation of NF-kB, JNK, and p38 signaling pathways. 71 In contrast, UBC13 À/À MEFs displayed no alteration in these signaling pathways relative to wild-type MEFs. 72 Although these discrepancies may be attributable to cell type-specific differences, experiments with UBC13 null cells suggest that other E2 enzymes may substitute for UBC13 in TNF-a signaling pathways.…”

Section: Dr Signaling Is Regulated By Ubiquitinationmentioning

confidence: 97%

Regulation of death receptor signaling by the ubiquitin system

Wertz¹,

Dixit²

2009

Cell Death Differ

112

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The study of death receptor (DR) signaling has led to the discovery of new signaling paradigms, including the first example of direct receptor-mediated activation of a protease (caspase-8) that functions as a second messenger to initiate a 'death cascade' of downstream protease activation. More recently, this receptor system has underscored the importance of ubiquitin modification in NF-jB activation. Both degradative lysine 48-linked polyubiquitin and scaffolding lysine 63-linked polyubiquitin have an essential role in signal propagation. Remarkably, a negative feedback process, termed ubiquitin editing, regulates signaling that emanates from certain DRs. Ubiquitin editing is mediated by a complex interplay between the ubiquitination and deubiquitination machinery, resulting in the replacement of signal enhancing lysine 63-linked polyubiquitin with signal extinguishing lysine 48-linked polyubiquitin. The ubiquitination machinery and its regulation in the context of DR signaling are discussed herein. The tumor necrosis factor receptor (TNFR) family is characterized by the presence of a variable number of cysteinerich domains within the extracellular segment and includes receptors known as the death receptors (DRs). The cognate ligands function in concert with the receptors to orchestrate immune responses, generate secondary lymphoid organs, and modulate the survival, proliferation, and differentiation of responding cells. When this axis goes awry, it can contribute to sepsis, cachexia, and autoimmune disorders including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. 1,2 Indeed, therapeutics based on neutralization of tumor necrosis factor-a (TNF-a) have met unparalleled success in the treatment of many autoimmune disorders. Furthermore, there has been a recent groundswell of enthusiasm for exploiting the proapoptotic properties of the DRs for TRAIL/ Apo2 ligand that selectively mediate the demise of tumor cells.There are six TNFR family DRs identified in humans to date: Fas/CD-95, TNFR1, DR3, DR4, DR5, and DR6. They are characterized by the presence of an B80-residue motif within their cytosolic segments dubbed the death domain (DD). 1,2 The integrity of this domain is essential for engaging downstream signaling components that, depending on the cellular context, promote either prosurvival and proinflammatory signaling pathways or promote apoptosis. 1,2 The DD is sixhelical fold that adopts a 'Greek key' topology and mediates homotypic interactions. There are four death-fold motifs: the DD itself, the death effector domain (DED), caspase activation and recruitment domain (CARD), and the Pyrin domain. 3 Although these folds all possess a similar topological configuration, their surface charge is distinct such that specificity of association is dictated by electrostatic interactions. 3 The DRs initiate signaling by recruiting one of two DD-containing platform adaptor molecules: FADD (Fas Associated Death Domain) that generally mediates apoptosis and/or TRADD (TNF Receptor Associated Death Domain)...

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Section: Dr Signaling Is Regulated By Ubiquitinationmentioning

confidence: 97%

Regulation of death receptor signaling by the ubiquitin system

Wertz¹,

Dixit²

2009

Cell Death Differ

112

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“…Ubc13 is also required for TRAF6 poly-ubiquitination and IKK activation in vivo, as spleen lysates from LPS-treated mice heterozygous for Ubc13 show lower poly-ubiquitination of TRAF6 than isolates from wild-type mice. IkBa degradation in response to LPS is also impaired in macrophages and splenocytes from Ubc13 +/-mice [43]. In contrast, Yamamoto et al revealed that Ubc13-deficient murine embryonic fibroblasts show normal activation of NF-kB in response to IL-1, whereas JNK activation is impaired [44].…”

Section: Il-1r and Tlr-4 Signaling To Nf-kbmentioning

confidence: 98%

“…Finally, TAB2, TAB3 and IKKg also become K63-poly-ubiquitinated by TRAF6 [22, 47 -49]. A role for oligomerization of TRAF6 in enhancing its ubiquitinating activity has also been postulated [39,42,43]. In fact, TRAF-interacting protein with a forkhead-associated domain (TIFA) was found to interact with TRAF6, thereby inducing TRAF6 oligomerization and enhancing TRAF6 ubiquitinating activity [50].…”

Section: Il-1r and Tlr-4 Signaling To Nf-kbmentioning

confidence: 99%

See 1 more Smart Citation

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

Verstrepen

Bekaert

Chau

et al. 2008

Cell. Mol. Life Sci.

398

297

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Abstract. Toll-like receptors (TLRs) as well as the receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-kB (NF-kB). TLR, IL-1R and TNF-R signaling to NF-kB converge on a common IkB kinase complex that phosphorylates the NF-kB inhibitory protein IkBa. However, upstream signaling components are in large part receptor-specific. Nevertheless, the principles of signaling are similar, involving the recruitment of specific adaptor proteins and the activation of kinase cascades in which protein-protein interactions are controlled by poly-ubiquitination. In this review, we will discuss our current knowledge of NF-kB signaling in response to TLR-4, TNF-R and IL-1R stimulation, with a special focus on the similarities and dissimilarities among these pathways.Keywords. Toll-like receptor 4, interleukin-1, tumor necrosis factor, NF-kB, signal transduction. NF-kB, does it still need to be introduced?Nuclear factor kB (NF-kB) is the generic name of a family of transcription factors that regulate the expression of a large number of genes involved in immune and inflammatory responses, as well as in cell survival, cell proliferation and cell differentiation. NFkB transcription factors are activated in response to various stimuli, including cytokines, infectious agents, injury and other stressful conditions requiring rapid reprogramming of gene expression. Inappropriate activation of the NF-kB signaling pathway is implicated in the pathogenesis of chronic inflammation and autoimmunity, certain hereditary disorders and various cancers. In mammals, the NF-kB family consists of five proteins sharing a highly conserved Rel homology domain: c-Rel, RelB, p65 (= RelA), p105 (= NF-kB1) and p100 (=NF-kB2). The first three contain Cterminal transactivation domains, while the others share a long C-terminal domain with multiple copies of ankyrin repeats, which inhibit their activation.

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“…8a) in LRRC19 and TRAF2 or TRAF6 co-expressing HEK293T cells. As TRAF6 and TRAF2 could be ubiquitinated in the process of signal transduction [26][27][28] , we hypothesized that the interaction of LRRC19 and TRAF6 or TRAF2 could affect the ubiquitination of TRAF6 and TRAF2. While the cells were transfected using Myc-tagged TRAF2 with control empty plasmid, degradation of TRAF2 could be observed (Fig.…”

Section: Lrrc19 Promotes Expression Of Antimicrobial Substancesmentioning

confidence: 99%

LRRC19 expressed in the kidney induces TRAF2/6-mediated signals to prevent infection by uropathogenic bacteria

Song

Cao

et al. 2014

Nat Commun

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The innate immune-dependent bactericidal effects are critical for preventing microbial colonization in the urinary system. However, the mechanisms involved in establishing innate immune responses in kidney are not completely understood. Here we describe the role of a novel member of the LRR (leucine-rich repeat) class of transmembrane proteins, LRRC19 (LRR-containing 19) in eliminating uropathogenic bacteria. LRRC19 is predominantly expressed in human and mouse kidney tubular epithelial cells and LRRC19-deficient mice are more susceptible to uropathogenic Escherichia coli (UPEC) infection than wild-type or TLR4 knockout mice. Recognition of UPEC by LRRC19 induces the production of cytokines, chemokines and antimicrobial substances through TRAF2-and TRAF6-mediated NF-kB and MAPK signalling pathways. Thus, LRRC19 may be a critical pathogen-recognition receptor in kidney mediating the elimination of UPEC infection.

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Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses

Cited by 104 publications

References 33 publications

Regulation of death receptor signaling by the ubiquitin system

Regulation of death receptor signaling by the ubiquitin system

TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

LRRC19 expressed in the kidney induces TRAF2/6-mediated signals to prevent infection by uropathogenic bacteria

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