The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20

Shembade, Noula; Harhaj, Nicole S.; Parvatiyar, Michelle S.; Copeland, Neal G.; Jenkins, Nancy A.; Matesic, Lydia E.; Harhaj, Edward W.

doi:10.1038/ni1563

Cited by 252 publications

(297 citation statements)

References 48 publications

Supporting

Mentioning

287

Contrasting

Order By: Relevance

“…Interestingly, we found that CYLD, ITCH, TNIP1, TNIP2 and TNIP3, the reported NF-κB-negative regulators [20,29,30], were also the potential targets of miR-486 ( Figure 3B, left panel). Indeed, immunoblotting analysis showed that overexpression of miR-486 repressed, while inhibition of miR-486 increased, the expression levels of CYLD, ITCH, TNIP1, TNIP2 and TNIP3 ( Figure 3B, right panel).…”

Section: Mir-486 Directly Suppresses Multiple Nf-κb Negative Regulatomentioning

confidence: 91%

“…How the negative regulatory effect of upregulated A20 on NF-κB signaling is disrupted in gliomas, however, remains unclear. Given that A20 does not have specificity for K63-linked polyubiquitin [29,30,36,37], have been proposed to participate in the NF-κB inhibitory effect of A20 through modulation of A20 activity. For example, ITCH has been found to terminate NF-κB signaling by controlling A20-mediated recruitment and inactivation of RIP1.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

Song

Lin²,

Gong³

et al. 2012

Cell Res

View full text Add to dashboard Cite

Deubiquitinases, such as CYLD, A20 and Cezanne, have emerged as important negative regulators that balance the strength and the duration of NF-κB signaling through feedback mechanisms. However, how these serial feedback loops are simultaneously disrupted in cancers, which commonly exhibit constitutively activated NF-κB, remains puzzling. Herein, we report that miR-486 directly suppresses NF-κB-negative regulators, CYLD and Cezanne, as well as multiple A20 activity regulators, including ITCH, TNIP-1, TNIP-2 and TNIP-3, resulting in promotion of ubiquitin conjugations in NF-κB signaling and sustained NF-κB activity. Furthermore, we demonstrate that upregulation of miR-486 promotes glioma aggressiveness both in vitro and in vivo through activation of NF-κB signaling pathway. Importantly, miR-486 levels in primary gliomas significantly correlate with NF-κB activation status. These findings uncover a novel mechanism for constitutive NF-κB activation in gliomas and support a functionally and clinically relevant epigenetic mechanism in cancer progression.

show abstract

Section: Mir-486 Directly Suppresses Multiple Nf-κb Negative Regulatomentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

Song

Lin²,

Gong³

et al. 2012

Cell Res

View full text Add to dashboard Cite

show abstract

“…Naf1 associates with A20, a zinc finger protein with deubiquitinase activity, and facilitates A20-mediated de-ubiquitination of NEMO/IKK␥ and subsequent NF-B inhibition in response of TNF-␣ (40,54,56). HIV-1-LTR contains the NF-B binding sites, and the suppression of Naf1 on NF-B activation may account for the inhibition of HIV-1 promoter LTR-driven gene expression and viral infection.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA

Ren

Wang

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

HIV-1 depends on host-cell-encoded factors to complete its life cycle. A comprehensive understanding of how HIV-1 manipulates host machineries during viral infection can facilitate the identification of host targets for antiviral drugs or gene therapy. The cellular protein Naf1 (HIV-1 Nef-associated factor 1) is a CRM1-dependent nucleo-cytoplasmic shuttling protein, and has been identified to regulate multiple receptor-mediated signal pathways in inflammation. The cytoplasm-located Naf1 can inhibit NF-B activation through binding to A20, and the loss of Naf1 controlled NF-B activation is associated with multiple autoimmune diseases. However, the effect of Naf1 on HIV-1 mRNA expression has not been characterized. In this study we found that the nucleus-located Naf1 could promote nuclear export of unspliced HIV-1 gag mRNA. We demonstrated that the association between Naf1 and CRM1 was required for this function as the inhibition or knockdown of CRM1 expression significantly impaired Naf1-promoted HIV-1 production. The mutation of Naf1 nuclear export signals (NESs) that account for CRM1 recruitment for nuclear export decreased Naf1 function. Additionally, the mutation of the nuclear localization signal (NLS) of Naf1 diminished its ability to promote HIV-1 production, demonstrating that the shuttling property of Naf1 is required for this function. Our results reveal a novel role of Naf1 in enhancing HIV-1 production, and provide a potential therapeutic target for controlling HIV-1 infection.HIV-1 depends on host factors to complete its life cycle (1-8). Hundreds of human proteins involved in the interaction with HIV-1 for modulating viral replication have been identified by genome-wide RNA interference screen or affinitytagged protein purification using mass spectrometry (1,(3)(4)9). A comprehensive understanding of how host machineries are manipulated during HIV-1 infection can facilitate the identification of host targets for antiviral drugs or gene therapy.The CRM1 (chromosome region maintenance 1, 2 also known as exportin 1) nuclear export pathway is typically used to transport host protein cargoes and small RNAs, which has been found to engage HIV-1 regulatory protein Rev for directing the nuclear export of unspliced and partially spliced HIV-1 RNAs (10 -15). These incompletely spliced HIV-1 RNAs contain a Rev response element (RRE), and the coordinate assembly of multiple Rev molecules on RRE recruits human protein complex containing CRM1 and Ran-GTP (GTP-binding nuclear protein Ran). Rev contains a leucine-rich nuclear export signal (NES) domain located near the carboxyl terminus, through which Rev interacts with CRM1, and the Rev-RRE-CRM1/Ran-GTP complex is then transported to the cytoplasm (6, 11-16). Similarly, other retroviruses such as mouse mammary tumor virus and human T cell lymphotropic virus encode Rev-like regulatory proteins Rem or Rex, respectively, for hijacking the host CRM1 pathway to accomplish nuclear export of unspliced viral transcripts (17)(18)(19)(20)(21)(22).Several other cellular facto...

show abstract

“…81 The RING domain E3 RNF11 was also reported to participate in the ubiquitin-mediated degradation of RIP1 after TNF-a treatment in collaboration with TAXBP1 and Itch. 82 The precise roles for each E3 recruited to the A20 ubiquitin-editing enzyme will be interesting to decipher.…”

Section: Dr Signaling Is Regulated By Ubiquitinationmentioning

confidence: 99%

Regulation of death receptor signaling by the ubiquitin system

Wertz¹,

Dixit²

2009

Cell Death Differ

111

View full text Add to dashboard Cite

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)...

show abstract

The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20

Cited by 252 publications

References 48 publications

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA

Regulation of death receptor signaling by the ubiquitin system

Contact Info

Product

Resources

About