SNX27-driven membrane localisation of OTULIN antagonises linear ubiquitination and NF-κB signalling activation

Abstract Background Linear ubiquitination is a novel type of ubiquitination that plays important physiological roles in signalling pathways such as tumour necrosis factor (TNF) signalling. However, little is known about the regulatory mechanisms of linear ubiquitination, except the well-described enzymatic regulators E3 ligase linear ubiquitin chain assembly complex (LUBAC) and deubiquitinase OTULIN. Results Previously, we identified SNX27, a member of the sorting nexin family protein, as a selective linear ubiquitin chain interactor in mass spectrometry-based ubiquitin interaction screening. Here, we demonstrated that the interaction between the linear ubiquitin chain and SNX27 is mediated by the OTULIN. Furthermore, we found that SNX27 inhibits LUBAC-mediated linear ubiquitin chain formation and TNFα-induced signalling activation. Mechanistic studies showed that, upon TNFα stimulation, OTULIN-SNX27 is localised to membrane-associated TNF receptor complex, where OTULIN deubiquitinates the linear polyubiquitin chain that formed by the LUBAC complex. Significantly, chemical inhibition of SNX27-retromer translocation by cholera toxin inhibits OTULIN membrane localization. Conclusions In conclusion, our study demonstrated that SNX27 inhibits TNFα induced NF-κB signalling activation via facilitating OTULIN to localize to TNF receptor complex.

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UXT-V1 protects cells against TNF-induced apoptosis through modulating complex II formation

Molecular Biology of the Cell ◽

10.1091/mbc.e10-10-0827 ◽

2011 ◽

Vol 22 (8) ◽

pp. 1389-1397 ◽

Cited By ~ 13

Author(s):

Yuefeng Huang ◽

Liang Chen ◽

Yi Zhou ◽

Heng Liu ◽

Jueqing Yang ◽

...

Keyword(s):

Tumor Necrosis ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Receptor Complex ◽

Tnf Receptor ◽

Death Domain ◽

Complex Ii ◽

Signaling Complex ◽

Induced Apoptosis ◽

Necrosis Factor

Proteins that directly regulate tumor necrosis factor (TNF) signaling have critical roles in determining cell death and survival. Previously we characterized ubiquitously expressed transcript (UXT)-V2 as a novel transcriptional cofactor to regulate nuclear factor-κB in the nucleus. Here we report that another splicing isoform of UXT, UXT-V1, localizes in cytoplasm and regulates TNF-induced apoptosis. UXT-V1 knockdown cells are hypersensitive to TNF-induced apoptosis. We demonstrated that UXT-V1 is a new component of TNF receptor signaling complex. We found that UXT-V1 binds to TNF receptor-associated factor 2 and prevents TNF receptor–associated death domain protein from recruiting Fas-associated protein with death domain. More importantly, UXT-V1 is a short-half-life protein, the degradation of which facilitates the formation of the apoptotic receptor complex II in response to TNF treatment. This study demonstrates that UXT-V1 is a novel regulator of TNF-induced apoptosis and sheds new light on the underlying molecular mechanism of this process.

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Assembly and Regulation of the CD40 Receptor Complex in Human B Cells

Journal of Experimental Medicine ◽

10.1084/jem.186.2.337 ◽

1997 ◽

Vol 186 (2) ◽

pp. 337-342 ◽

Cited By ~ 65

Author(s):

Michelle R. Kuhné ◽

Michael Robbins ◽

John E. Hambor ◽

Matthew F. Mackey ◽

Yoko Kosaka ◽

...

Keyword(s):

Cell Differentiation ◽

B Cells ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Receptor Complex ◽

Tnf Receptor ◽

B Cell Differentiation ◽

Membrane Immunoglobulin ◽

Human B Cells ◽

Necrosis Factor

CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily. Studies with human B cells show that the binding of CD154 (gp39, CD40L) to CD40 recruits TNF receptor– associated factor 2 (TRAF2) and TRAF3 to the receptor complex, induces the downregulation of the nonreceptor-associated TRAFs in the cell and induces an increased expression of Fas on the cell surface. Combined signaling through the interluekin 4 receptor and CD40 induces an increased expression of Fas with a commensurate increase in the level of TRAF2, but not TRAF3, that is recruited to the receptor complex. In contrast, engagement of the membrane immunoglobulin and CD40 limits Fas upregulation and reduces the recruitment of TRAF2, relative to TRAF3, to the CD40 receptor complex. These studies show that the TRAF composition of the CD40 receptor complex can be altered by signals that influence B cell differentiation.

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The ubiquitin ligase HOIL-1L regulates immune responses by interacting with linear ubiquitin chains

10.1101/2021.04.13.439587 ◽

2021 ◽

Author(s):

Carlos Gomez Diaz ◽

Gustav Jonsson ◽

Katrin Schodl ◽

Luiza Deszcz ◽

Annika Bestehorn ◽

...

Keyword(s):

Immune Responses ◽

Cytokine Production ◽

Physiological Role ◽

Skin Inflammation ◽

Cell Types ◽

Tnf Receptor ◽

Ubiquitin Chain ◽

Regulatory Functions ◽

Necrosis Factor

The Linear Ubiquitin Assembly Complex (LUBAC), composed of HOIP, HOIL-1L and SHARPIN, promotes Tumor Necrosis Factor (TNF)-dependent NF-kB signaling in diverse cell types. HOIL-1L contains an Npl4 Zinc Finger (NZF) domain that specifically recognizes linear ubiquitin chains, but its physiological role in vivo has remained unclear. Here, we demonstrate that the HOIL-1L NZF domain has important regulatory functions in inflammation and immune responses in mice. We generated knockin mice (Hoil-1lT20;A;R208A/T201A;R208A) expressing a HOIL-1L NZF mutant, and observed attenuated responses to TNF- and LPS-induced shock, including prolonged survival, stabilized body temperature, reduced cytokine production and liver damage markers. Cells derived from the HOIL-1L knockin mice show reduced TNF-dependent NF-kB activation and incomplete recruitment of HOIL-1L into TNF Receptor (TNFR) Complex I. We further show that the HOIL-1L-NZF domain cooperates with SHARPIN to prevent TNFR-dependent skin inflammation. Collectively, our data suggest that linear ubiquitin-chain binding by HOIL-1L regulates immune responses and inflammation in vivo.

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The α and β Subunits of IκB Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF

Molecular and Cellular Biology ◽

10.1128/mcb.21.12.3986-3994.2001 ◽

2001 ◽

Vol 21 (12) ◽

pp. 3986-3994 ◽

Cited By ~ 100

Author(s):

Anne Devin ◽

Yong Lin ◽

Shoji Yamaoka ◽

Zhiwei Li ◽

Michael Karin ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Leucine Zipper ◽

Nuclear Translocation ◽

Ring Finger ◽

Tnf Receptor ◽

Death Domain ◽

Iκb Kinase ◽

Cytokine Tumor Necrosis Factor ◽

Necrosis Factor

ABSTRACT The activation of IκB kinase (IKK) is a key step in the nuclear translocation of the transcription factor NF-κB. IKK is a complex composed of three subunits: IKKα, IKKβ, and IKKγ (also called NEMO). In response to the proinflammatory cytokine tumor necrosis factor (TNF), IKK is activated after being recruited to the TNF receptor 1 (TNF-R1) complex via TNF receptor-associated factor 2 (TRAF2). We found that the IKKα and IKKβ catalytic subunits are required for IKK-TRAF2 interaction. This interaction occurs through the leucine zipper motif common to IKKα, IKKβ, and the RING finger domain of TRAF2, and either IKKα or IKKβ alone is sufficient for the recruitment of IKK to TNF-R1. Importantly, IKKγ is not essential for TNF-induced IKK recruitment to TNF-R1, as this occurs efficiently in IKKγ-deficient cells. Using TRAF2−/− cells, we demonstrated that the TNF-induced interaction between IKKγ and the death domain kinase RIP is TRAF2 dependent and that one possible function of this interaction is to stabilize the IKK complex when it interacts with TRAF2.

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Membrane lymphotoxin-α2β is a novel tumor necrosis factor (TNF) receptor 2 (TNFR2) agonist

Cell Death and Disease ◽

10.1038/s41419-021-03633-8 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Kirstin Kucka ◽

Isabell Lang ◽

Tengyu Zhang ◽

Daniela Siegmund ◽

Juliane Medler ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Asymmetric Structure ◽

Tnf Receptor ◽

Membrane Bound ◽

Necrosis Factor

AbstractIn the early 1990s, it has been described that LTα and LTβ form LTα2β and LTαβ2 heterotrimers, which bind to TNFR1 and LTβR, respectively. Afterwards, the LTαβ2–LTβR system has been intensively studied while the LTα2β–TNFR1 interaction has been ignored to date, presumably due to the fact that at the time of identification of the LTα2β–TNFR1 interaction one knew already two ligands for TNFR1, namely TNF and LTα. Here, we show that LTα2β interacts not only with TNFR1 but also with TNFR2. We furthermore demonstrate that membrane-bound LTα2β (memLTα2β), despite its asymmetric structure, stimulates TNFR1 and TNFR2 signaling. Not surprising in view of its ability to interact with TNFR2, LTα2β is inhibited by Etanercept, which is approved for the treatment of rheumatoid arthritis and also inhibits TNF and LTα.

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Tumor necrosis factor-α inhibitors alleviation of experimentally induced neuropathic pain is associated with modulation of TNF receptor expression

Journal of Neuroscience Research ◽

10.1002/jnr.23432 ◽

2014 ◽

Vol 92 (11) ◽

pp. 1490-1498 ◽

Cited By ~ 16

Author(s):

Pablo Andrade ◽

Govert Hoogland ◽

John S. Del Rosario ◽

Harry W. Steinbusch ◽

Veerle Visser-Vandewalle ◽

...

Keyword(s):

Neuropathic Pain ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Receptor Expression ◽

Tnf Receptor ◽

Factor Α ◽

Necrosis Factor ◽

Experimentally Induced

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Molecular cloning, expression and functional characterization of tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein (TRIP) in grass carp, Ctenopharyngodon idella

Fish & Shellfish Immunology ◽

10.1016/j.fsi.2016.08.041 ◽

2016 ◽

Vol 57 ◽

pp. 406-412

Author(s):

R.-H. Lu ◽

Z.-G. Chang ◽

J. Sun ◽

F. Yang ◽

G.-X. Nie ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Grass Carp ◽

Tumor Necrosis ◽

Functional Characterization ◽

Ctenopharyngodon Idella ◽

Tnf Receptor ◽

Interacting Protein ◽

Grass Carp Ctenopharyngodon Idella ◽

Necrosis Factor

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Tumor necrosis factor receptor-mediated apoptosis in Trichinella spiralis-infected muscle cells

Parasitology ◽

10.1017/s0031182005007663 ◽

2005 ◽

Vol 131 (3) ◽

pp. 373-381 ◽

Cited By ~ 21

Author(s):

Z. WU ◽

I. NAGANO ◽

T. BOONMARS ◽

Y. TAKAHASHI

Keyword(s):

Caspase 3 ◽

Trichinella Spiralis ◽

Cell Formation ◽

Muscle Cells ◽

Cyst Formation ◽

Signalling Pathway ◽

Tnf Receptor ◽

Tnf Α ◽

Infected Muscle ◽

Necrosis Factor

In order to reveal the mechanisms underlying nurse cell formation during Trichinella spiralis infection, the expression of the factors of tumor necrosis factor-alpha (TNF-α)/TNF receptor 1 (TNFR-1) signalling pathway mediating apoptosis was investigated. The analysed factors included TNF-α, TNFR-1, TNF receptor-associated death-domain (TRADD), caspase 3, caspase 8, TNF receptor associated factor-2 (TRAF2) and receptor interactive protein (RIP), all of which are involved in the TNF-α/TNFR-1 signalling pathway-mediated apoptosis. The quantitative RT-PCR indicated that the infected muscle tissues up-regulate the expression of pro-apoptosis genes (TNF-α, TNFR-1 and TRADD, caspase 3 and caspase 8), and anti-apoptosis genes (TRAF2 and RIP) at the beginning of cyst formation. The expression returned to the normal level after cyst formation. The quantitative RT-PCR analysis of mRNA from tissue samples isolated by laser capture micro-dissection confirmed that the up-regulation of these genes was restricted in infected muscle cells, was not in the inflammation cells around infected muscle cells nor in normal muscle cells. The in situ localization study of pro-apoptosis (TRADD, caspase 3) and anti-apoptosis gene products (TRAF2) indicated that these were expressed in the basophilic cytoplasm (infected muscle cell origin) of the nurse cells. Thus the present study suggests that the TNF-α/TNFR-1 signalling pathway is involved in nurse cell formation.

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