α/NOX/iNOS Signalling Pathway in ... - Heidelberg University
Signalling: Filling in the blanks in NF-κB signalling
1
HIGHLIGHTS NATURE REVIEWS | IMMUNOLOGY VOLUME 4 | JUNE 2004 | 399 HIGHLIGHT ADVISORS CEZMI AKDIS SWISS INSTITUTE OF ALLERGY AND ASTHMA RESEARCH, SWITZERLAND BRUCE BEUTLER SCRIPPS RESEARCH INSTITUTE, USA PETER CRESSWELL YALE UNIVERSITY, USA JAMES DI SANTO PASTEUR INSTITUTE, FRANCE GARY KORETZKY UNIVERSITY OF PENNSYLVANIA, USA CHARLES MACKAY GARVAN INSTITUTE OF MEDICAL RESEARCH, AUSTRALIA CORNELIS J. M. MELIEF LEIDEN UNIVERSITY MEDICAL CENTRE, THE NETHERLANDS MICHEL NUSSENZWEIG THE ROCKEFELLER UNIVERSITY, USA SARAH ROWLAND-JONES CENTRE FOR TROPICAL MEDICINE, OXFORD, UK ALAN SHER NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASE, USA ANDREAS STRASSER THE WALTER AND ELIZA HALL INSTITUTE, AUSTRALIA MEGAN SYKES HARVARD MEDICAL SCHOOL, USA ERIC VIVIER CENTRE D’IMMUNOLOGIE DE MARSEILLE-LUMINY, FRANCE MATTHIAS VON HERRATH LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY, USA. The mechanism of activation of the kinase complex IKK — which regu- lates IκB, the inhibitory molecule that controls nuclear factor-κB (NF-κB) activation — during anti- gen-receptor signalling in T cells has not been well understood to date. But now, a study published in Molecular Cell shows that the ubiq- uitin ligase TRAF6 and the kinase TAK1 have important roles in mediating IKK activation by BCL-10 and MALT1. The classical pathway for activa- tion of the transcription factor NF-κB in T cells is controlled by the IKK complex. This complex consists of two active kinases (IKK-α and IKK-β) and a regulatory molecule known as IKK-γ or NEMO. Activation of the IKK complex leads to phosphoryla- tion of IκBα, which is ubiquitylated and degraded by the proteasome, allowing NF-κB to translocate to the nucleus and activate gene transcrip- tion. It has recently been shown that CARMA1, BCL-10 and MALT1 are important components of this sig- nalling pathway downstream of the antigen receptor and upstream of the IKK complex. To address the mechanism of IKK activation, the authors developed a cell-free system based on cytosolic extracts, in which IKK is activated by addition of recombinant BCL-10. They initially showed that the ubiquitin-conjugating enzyme com- plex UBC13–UEV1A has a role in IKK activation. When UEV1A was depleted from cell extracts using Sepharose beads coated with UBC13, addition of recombinant complex to the depleted extracts did not restore IKK activation by BCL-10, indicating that another factor that interacts with UBC13 was also removed. By analysis of the molecules eluted from the UBC13-coated beads, this factor was identified as TRAF6. In addition to TRAF6, RNA interfer- ence and dominant-negative experi- ments showed that MALT1, TRAF2 and the kinase TAK1 are also required for IKK activation. TRAF6 was found to mediate polyubiquitylation of IKK-γ. Further experiments revealed that a fraction of BCL-10 and MALT1 formed oligomeric complexes and that only these multimerized forms can activate IKK. The authors also showed that oligomerization of TRAF6 activates its ubiquitin ligase activity and that oligomerization of MALT1 is required for TRAF6 oligomerization. The results in this study support a model of IKK activation in which antigen-receptor signalling results in activation of protein kinase C-θ (PKC-θ), recruitment of BCL-10 to the synapse, followed by oligomer- ization of BCL-10, MALT1 and TRAF6. TRAF6 then polyubiquity- lates itself and other substrates, such as IKK-γ, leading to the activa- tion of TAK1 and the recruitment of TAK1 to the IKK complex. TAK1 can then phosphorylate IKK-β and activate IKK (see figure). Elaine Bell References and links ORIGINAL RESEARCH PAPER Sun, L. et al. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol. Cell 14, 289–301 (2004) FURTHER READING Thome, M. CARMA1, BCL-10 and MALT1 in lymphocyte development and activation. Nature Rev. Immunol. 4, 348–359 (2004) P P T-cell receptor IKK ? β α γ Activated IKK β α CD28 CARMA1 BCL-10 MALT1 TAB TAK1 CARMA1 BCL-10 MALT1 PKC-θ SRC and SYK kinases TRAF6 Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub TRAF6 γ Filling in the blanks in NF-κB signalling SIGNALLING IKK activation in T cells is controlled by an oligomerization–ubiquitylation (Ub)–phosphorylation pathway.
Transcript of Signalling: Filling in the blanks in NF-κB signalling
HIGHLIGHTS
NATURE REVIEWS | IMMUNOLOGY VOLUME 4 | JUNE 2004 | 399
HIGHLIGHT ADVISORS
CEZMI AKDIS
SWISS INSTITUTE OF ALLERGYAND ASTHMA RESEARCH,SWITZERLAND
BRUCE BEUTLER
SCRIPPS RESEARCH INSTITUTE,USA
PETER CRESSWELL
YALE UNIVERSITY, USA
JAMES DI SANTO
PASTEUR INSTITUTE, FRANCE
GARY KORETZKY
UNIVERSITY OFPENNSYLVANIA, USA
CHARLES MACKAY
GARVAN INSTITUTE OFMEDICAL RESEARCH,AUSTRALIA
CORNELIS J. M. MELIEF
LEIDEN UNIVERSITY MEDICALCENTRE, THE NETHERLANDS
MICHEL NUSSENZWEIG
THE ROCKEFELLER UNIVERSITY,USA
SARAH ROWLAND-JONES
CENTRE FOR TROPICALMEDICINE, OXFORD, UK
ALAN SHER
NATIONAL INSTITUTE OFALLERGY AND INFECTIOUSDISEASE, USA
ANDREAS STRASSER
THE WALTER AND ELIZA HALLINSTITUTE, AUSTRALIA
MEGAN SYKES
HARVARD MEDICAL SCHOOL,USA
ERIC VIVIER
CENTRE D’IMMUNOLOGIE DEMARSEILLE-LUMINY, FRANCE
MATTHIAS VON HERRATH
LA JOLLA INSTITUTE FORALLERGY AND IMMUNOLOGY,USA.
The mechanism of activation of thekinase complex IKK — which regu-lates IκB, the inhibitory moleculethat controls nuclear factor-κB(NF-κB) activation — during anti-gen-receptor signalling in T cellshas not been well understood todate. But now, a study published inMolecular Cell shows that the ubiq-uitin ligase TRAF6 and the kinaseTAK1 have important roles inmediating IKK activation by BCL-10and MALT1.
The classical pathway for activa-tion of the transcription factor NF-κBin T cells is controlled by the IKKcomplex. This complex consists oftwo active kinases (IKK-α and IKK-β)and a regulatory molecule known asIKK-γ or NEMO. Activation of theIKK complex leads to phosphoryla-tion of IκBα, which is ubiquitylatedand degraded by the proteasome,allowing NF-κB to translocate to thenucleus and activate gene transcrip-tion. It has recently been shown thatCARMA1, BCL-10 and MALT1 areimportant components of this sig-nalling pathway downstream of theantigen receptor and upstream of theIKK complex.
To address the mechanism of IKKactivation, the authors developed acell-free system based on cytosolicextracts, in which IKK is activated byaddition of recombinant BCL-10.They initially showed that the ubiquitin-conjugating enzyme com-plex UBC13–UEV1A has a role inIKK activation. When UEV1A wasdepleted from cell extracts using
Sepharose beads coated with UBC13,addition of recombinant complex tothe depleted extracts did not restoreIKK activation by BCL-10, indicatingthat another factor that interactswith UBC13 was also removed. Byanalysis of the molecules elutedfrom the UBC13-coated beads, thisfactor was identified as TRAF6. Inaddition to TRAF6, RNA interfer-ence and dominant-negative experi-ments showed that MALT1, TRAF2and the kinase TAK1 are also requiredfor IKK activation. TRAF6 was foundto mediate polyubiquitylation ofIKK-γ.
Further experiments revealed thata fraction of BCL-10 and MALT1formed oligomeric complexes andthat only these multimerized formscan activate IKK. The authors alsoshowed that oligomerization ofTRAF6 activates its ubiquitin ligaseactivity and that oligomerization ofMALT1 is required for TRAF6oligomerization.
The results in this study supporta model of IKK activation in whichantigen-receptor signalling resultsin activation of protein kinase C-θ(PKC-θ), recruitment of BCL-10 tothe synapse, followed by oligomer-ization of BCL-10, MALT1 andTRAF6. TRAF6 then polyubiquity-lates itself and other substrates,such as IKK-γ, leading to the activa-tion of TAK1 and the recruitmentof TAK1 to the IKK complex. TAK1can then phosphorylate IKK-β andactivate IKK (see figure).
Elaine Bell
References and linksORIGINAL RESEARCH PAPER Sun, L. et al.The TRAF6 ubiquitin ligase and TAK1 kinasemediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol. Cell 14, 289–301 (2004)FURTHER READING Thome, M. CARMA1,BCL-10 and MALT1 in lymphocyte developmentand activation. Nature Rev. Immunol. 4, 348–359(2004)
P
P
T-cell receptor
IKK
?
β
αγ
Activated IKK
β
α
CD28
CARMA1
BCL-10
MALT1
TAB TAK1
CARMA1
BCL-10
MALT1
PKC-θ
SRC and SYKkinases
TRAF6
UbUb
Ub
UbUb
Ub
UbUbUb
Ub UbUb
Ub TRAF6
γ
Filling in the blanks in NF-κB signalling
S I G N A L L I N G
IKK activation in T cells is controlled by anoligomerization–ubiquitylation (Ub)–phosphorylationpathway.
![Mechanisms and functions of p38 MAPK signalling and functions of p38 MAPK signalling 405 Both MKK3 and MKK6 are highly specific for p38 MAPKs [14,23].Inaddition,p38αcanbealsophophorylatedbyMKK4,an](https://static.fdocument.org/doc/165x107/5ae2800d7f8b9a097a8d0b79/mechanisms-and-functions-of-p38-mapk-signalling-and-functions-of-p38-mapk-signalling.jpg)
