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Interaction of calmodulin with Bcl10 modulates NF-kappaB activation.
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). (Grundström)
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). (Grundström)
Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). (Grundström)
2010 (Engelska)Ingår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 47, nr 11-12, s. 2057-2064Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Calcium signals resulting from antigen receptor activation are important in determining the responses of a T or B lymphocyte to an antigen. Calmodulin (CaM), a multi-functional sensor of intracellular calcium (Ca(2+)) signals in cells, is required in the pathway from the T cell receptor (TCR) to activation of the key transcription factor NF-kappaB. Here we searched for a partner in direct interaction with CaM in the pathway, and found that CaM interacts specifically with the signaling adaptor Bcl10. The binding is Ca(2+) dependent and of high affinity, with a K(d) of approximately 160 nM. Proximity of CaM and Bcl10 in vivo is induced by increases in the intracellular Ca(2+) level. The interaction is localized to the CARD domain of Bcl10, which interacts with the CARD domain of the upstream signaling partner Carma1. Binding of CaM to Bcl10 is shown to inhibit the ability of Bcl10 to interact with Carma1, an interaction that is required for signaling from the TCR to NF-kappaB. Furthermore, a mutant of Bcl10 with reduced binding to CaM shows increased activation of an NF-kappaB reporter, which is further enhanced by activating stimuli. We propose a novel mechanism whereby the Ca(2+) sensor CaM regulates T cell responses to antigens by binding to Bcl10, thereby modulating its interaction with Carma1 and subsequent activation of NF-kappaB.

Ort, förlag, år, upplaga, sidor
Elsevier , 2010. Vol. 47, nr 11-12, s. 2057-2064
Nyckelord [en]
Gene regulation, Signal transduction, NF-κB, Bcl10, Carma1, Calmodulin, Calcium signaling
Nationell ämneskategori
Medicin och hälsovetenskap
Forskningsämne
medicin
Identifikatorer
URN: urn:nbn:se:umu:diva-35923DOI: 10.1016/j.molimm.2010.04.005ISI: 000279578800014PubMedID: 20439115OAI: oai:DiVA.org:umu-35923DiVA, id: diva2:350003
Tillgänglig från: 2010-09-09 Skapad: 2010-09-09 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Regulation of activation of NF-κB by Calmodulin in T-lymphocytes
Öppna denna publikation i ny flik eller fönster >>Regulation of activation of NF-κB by Calmodulin in T-lymphocytes
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Nuclear factor kappa B (NF-kB) is a widely expressed family of transcription factors that are involved in a diverse number of processes. These include inflammation or differentiation, survival or apoptosis, and proliferation or cell cycle arrest. NF-kB is usually associated with inhibitory kB proteins (IkB), which mask the nuclear localisation sequence (NLS) of NF-kB and renders it in the cytoplasm. Various stimuli result in the activation of the I kappa B kinase (IKK) protein complex, which phosphorylates IκB proteins and thereby marks them for degradation by the ubiquitin-proteasome pathway. Thereby NF-kB enters the nucleus and acts on its target genes. The study of T- and B-lymphocyte antigen receptor signalling to NF-kB is a field of intense investigation, with much attention being focused on the molecular scaffolding proteins Carma1, Bcl10 and MALT1 and their post-translational modifications. These have been shown to be crucial for the organization of the immunological synapse structure under the activated receptor, to which IKK is recruited and becomes activated, which subsequently leads to the activation of NF-kB.

T cell receptor (TCR) activation results in a rapid increase in the intracellular Ca2+ level and NF-kB activation is known to be regulated by those increases, but the mechanisms have remained unclear. Calmodulin (CaM) is a calcium sensory protein that responds to increases in intracellular Ca2+ levels. When CaM binds Ca2+ ions, it leads to structural changes that directly as well as indirectly, through CaM dependent kinases (CaMKs), phosphatases and other enzymes, alters a variety of cellular processes, among them transcriptional regulation. Here CaM is shown to interact directly with Bcl10 in a Ca2+ dependent manner. Increases in the intracellular Ca2+ level are shown to induce the proximity of Bcl10 and CaM in vivo. Carma1 associates with Bcl10 through a CARD-CARD domain interaction that is known to be crucial for TCR signalling to NF-kB. The interaction of CaM with Bcl10 was mapped to the CARD domain and was shown to be a negative regulator for the Bcl10-Carma1 interaction. Inhibition of the CaM interaction by a point mutation within the CaM binding site of Bcl10 results in decreased binding of CaM to Bcl10 in vivo, as well as an increased ability of Bcl10 to induce NF-kB transcriptional activity, which is further enhanced by TCR activating stimuli.

NF-kB activation is also shown here to be regulated by CaM indirectly through actions of CaMKII. The CaMKII is recruited to the immunological synapse where it interacts with Bcl10 in an inducible fashion and phosphorylates Bcl10. Phosphorylations of Bcl10 by CaMKII are shown to be important for the ability of Bcl10 to induce NF-κB transcriptional activity. Upon mutation of its most important CaMKII site, Bcl10 fails to activate an NF-kB reporter and an NF-kB target gene (IL-2). This mutated Bcl10 also fails to induce activating phosphorylations of IKKa/b and the kinase JNK2 but not JNK1. Furthermore, phosphorylation of Bcl10 by CaMKII regulates the interactions within the important Carma1, Bcl10, Malt1 signaling complex and the essential signal induced ubiquitinations of Bcl10 and IKKg. Phosphorylation of IKK by TAK1 is also regulated by CaMKII, and serine 82 is a putative CaMKII target site of TAK1 that appears to be important for IκBα degradation.

In summary, this thesis explores that not only NF-kB but also CaM is a double-edged sword, since the multi-functional NF-kB family of transcription factors is regulated by CaM both negatively and positively.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå university, 2011. s. 75
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1445
Nyckelord
Calcium, Calmodulin, CaMKII, TCR, Bcl10, NF-κB
Identifikatorer
urn:nbn:se:umu:diva-46561 (URN)978-91-7459-278-8 (ISBN)
Disputation
2011-09-27, Major Groove, Byggnad 6L, Umeå University, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2011-09-06 Skapad: 2011-09-05 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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