TRAF6-mediated ubiquitination regulates nuclear translocation of NRIF, the p75 receptor interactor

Geetha, Thangiah; Kenchappa, Rajappa S.; Wooten, Marie W.; Carter, Bruce D.

doi:10.1038/sj.emboj.7600845

Cited by 83 publications

(88 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conserved sequences flanking the TRAF6/p62 ubiquitin acceptor site Two independent reports have identified TrkA [9] and NRIF [10] as TRAF6/p62 substrates. Moreover, the specific lysine residue in both these proteins that serve as the ubiquitin acceptor site was identified.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Identification of a consensus site for TRAF6/p62 polyubiquitination

Jadhav

Geetha

Jiang

et al. 2008

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an ubiquitin ligase that regulates a diverse array of physiological processes via forming Lys-63 linked polyubiquitin chains. In this study, the lysine selection process for TRAF6/p62 ubiquitination was examined. The protein sequence of two characterized TRAF6/p62 substrates, NRIF and TrkA, revealed a conserved consensus pattern for the ubiquitination site of these two TRAF6 substrates. The consensus pattern established in the verified substrates was common to the other Trk receptor family members, TrkB and TrkC. Interestingly, Lysine 811 in TrkB was selected for ubiquination, and mutation of Lysine 811 diminished the formation of TRAF6/p62 complex that is necessary for effective ubiquination. Moreover, downstream signaling was affected upon binding of BDNF to the mutant TrkB receptor. These findings reveal a possible selection process for targeting a specific lysine residue by a single E3 ligase and underscore the role of the scaffold, p62, in this process. KeywordsUbiquitination; Ub ligase; TRAF6; p62; Trk Many adaptors have been identified in studies of other neuronal tyrosine kinases that may also prove to function in Trk receptor-mediated signaling [1]. Cytoplasmic protein p62 was identified as an interacting partner of atypical protein kinase C (PKC) [2] and has been shown to contain several protein-protein interacting modules that enable the protein to serve as a scaffold for activation of the transcription factor NF-κB [3]. The multidomain protein structure of p62 is suggestive of diverse protein-protein interactions and its link in cellular functions. The functional motifs in p62 include a Phox and Bem1p domain (PB1) domain that embeds an octicosapeptide Phox, Cdc and the atypical PKC-interaction domain (AID) (OPCA) motif, a ZZ zinc finger, a binding site for Tumor necrosis factor Receptor-Associated Factor 6 (TRAF6), two PEST sequences, and an Ubiquitin-associated (UBA) domain [4]. The Cterminal ubiquitin-associated domain (UBA) was discovered to bind non-covalently to ubiquitin [5]. In vitro binding studies have unveiled p62 as a unique ubiquitin-binding protein, which binds polyubiquitin non-covalently through its C-terminus [6].Ubiquitination of eukaryotic proteins regulates a broad range of cellular processes. E3 Ub ligases are known to interact with specific substrates either directly or through adaptor proteins. *Corresponding author. Fax: +1 (334) 844-5255, Email address: wootemw@auburn.edu (M. Wooten). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. . High substrate specificity of the ...

show abstract

Section: Resultsmentioning

confidence: 99%

“…Recent findings from our lab have revealed that both TrkA [9] and the neurotrophin receptor interacting factor (NRIF) [10] are K63-polyubiquitinated by the TRAF6/p62 complex. Mutation analyses of these proteins identified a single acceptor lysine residue that serves as the recognition site for polyubiquitination.…”

mentioning

confidence: 99%

Identification of a consensus site for TRAF6/p62 polyubiquitination

Jadhav

Geetha

Jiang

et al. 2008

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

show abstract

“…The atypical protein kinase Cs (aPKCs) bind to p62 and other proteins to stimulate the activation of the transcription factor NF-B (47,48), which plays an important role in regulating genes involved in neuronal development and survival (49). In addition, p62 functions as a scaffold for nerve growth factor receptor p75 (47) as well as intracellular p75 effector NRIF (50). It remains unknown whether and how the above signaling pathways, in which p62 participates, change in mutant SOD1-mediated fALS.…”

Section: Discussionmentioning

confidence: 99%

p62 Accumulates and Enhances Aggregate Formation in Model Systems of Familial Amyotrophic Lateral Sclerosis

Gál

Ström

Kilty

et al. 2007

Journal of Biological Chemistry

155

122

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron death. A hallmark of the disease is the appearance of protein aggregates in the affected motor neurons. We have found that p62, a protein implicated in protein aggregate formation, accumulated progressively in the G93A mouse spinal cord. The accumulation of p62 was in parallel to the increase of polyubiquitinated proteins and mutant SOD1 aggregates. Immunostaining studies showed that p62, ubiquitin, and mutant SOD1 co-localized in the protein aggregates in affected cells in G93A mouse spinal cord. The p62 protein selectively interacted with familial ALS mutants, but not WT SOD1. When p62 was co-expressed with SOD1 in NSC34 cells, it greatly enhanced the formation of aggregates of the ALS-linked SOD1 mutants, but not wild-type SOD1. Cell viability was measured in the presence and absence of overexpressed p62, and the results suggest that the large aggregates facilitated by p62 were not directly toxic to cells under the conditions in this study. Deletion of the ubiquitin-association (UBA) domain of p62 significantly decreased the p62-facilitated aggregate formation, but did not completely inhibit it. Further protein interaction experiments also showed that the truncated p62 with the UBA domain deletion remained capable of interacting with mutant SOD1. The findings of this study show that p62 plays a critical role in forming protein aggregates in familial ALS, likely by linking misfolded mutant SOD1 molecules and other cellular proteins together. Amyotrophic lateral sclerosis (ALS)3 is a progressive neurodegenerative disorder leading to the selective death of motor neurons (1, 2). The majority of cases are sporadic, but about 10% of all cases are familial (fALS). In ϳ20% of familial cases, a mutant allele of the copper-zinc superoxide dismutase (SOD1) enzyme has been identified (3-5). As of today, over 100 different mutations of SOD1 causing ALS have been reported, the majority of which are point mutations and act in a dominant fashion. Several ALS risk factors have been identified, but the etiology of the disease is largely unclear. A hallmark of the disease is the appearance of intracellular inclusions in degenerating motor neurons (6), both in the familial cases caused by mutations in SOD1 and in the more obscure sporadic cases (6 -11). The formation of such protein aggregates precedes neuronal death (12). The inclusions are typically SOD1 and ubiquitin immunoreactive in the mutant SOD1-mediated fALS cases (2, 7-9, 11-13). However, it is unclear how the SOD1 mutants form aggregates and whether other proteins play any role in the aggregation process or the aggregate-induced toxicity.p62 (also called sequestosome 1) was first identified as a phosphotyrosine-independent ligand for the Lck SH2 domain (14). It was later found to be a polyubiquitin-binding protein (15)(16)(17). The expression of p62 is up-regulated by several stress conditions, e.g. oxidative stress (18,19), proteasome inhibition (19 -21), or p...

show abstract

“…65,2008 Review Article 2967 ulation is impaired [44]. As UbcH7 is also known to mediate K63-linked poly-ubiquitination of TRAF6 [45], there might be redundancy for TRAF6 autoubiquitination, but not for IKKg poly-ubiquitination by TRAF6. Furthermore, RNA interference-mediated knock-down of either Ubc13 or Uev1A abolishes TRAF6-induced NF-kB activation, IKKg poly-ubiquitination and p65 nuclear translocation upon LPS stimulation [46].…”

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

confidence: 99%

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.

386

286

View full text Add to dashboard Cite

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.

show abstract

TRAF6-mediated ubiquitination regulates nuclear translocation of NRIF, the p75 receptor interactor

Cited by 83 publications

References 48 publications

Identification of a consensus site for TRAF6/p62 polyubiquitination

Identification of a consensus site for TRAF6/p62 polyubiquitination

p62 Accumulates and Enhances Aggregate Formation in Model Systems of Familial Amyotrophic Lateral Sclerosis

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

Contact Info

Product

Resources

About