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Grundström, Christine
Publications (10 of 13) Show all publications
Grundström, C., Kumar, A., Priya, A., Negi, N. & Grundström, T. (2018). ETS1 and PAX5 transcription factors recruit AID to Igh DNA. European Journal of Immunology, 48(10), 1687-1697
Open this publication in new window or tab >>ETS1 and PAX5 transcription factors recruit AID to Igh DNA
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2018 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 48, no 10, p. 1687-1697Article in journal (Refereed) Published
Abstract [en]

B lymphocytes optimize antibody responses by class switch recombination (CSR), which changes the expressed constant region exon of the immunoglobulin heavy chain (IgH), and by somatic hypermutation (SH) that introduces point mutations in the variable regions of the antibody genes. Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates both these antibody diversification processes by deaminating cytosine to uracil. Here we asked the question if transcription factors can mediate the specific targeting of the antibody diversification by recruiting AID. We have recently reported that AID is together with the transcription factors E2A, PAX5 and IRF4 in a complex on key sequences of the Igh locus. Here we report that also ETS1 is together with AID in this complex on key sequences of the Igh locus in splenic B cells of mice. Furthermore, we show that both ETS1 and PAX5 can directly recruit AID to DNA sequences from the Igh locus with the specific binding site for the transcription factor. Taken together, our findings support the notion of a targeting mechanism for the selective diversification of antibody genes with limited genome wide mutagenesis by recruitment of AID by PAX5 and ETS1 in a transcription factor complex.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018
Keywords
Activation-induced cytidine deaminase, Class switch recombination, Protein interactions, Somatic hypermutation, Transcription factors
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-152886 (URN)10.1002/eji.201847625 (DOI)000446431600008 ()30089192 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2018-10-31 Created: 2018-10-31 Last updated: 2018-10-31Bibliographically approved
Kumar, A., Priya, A., Ahmed, T., Grundström, C., Negi, N. & Grundström, T. (2018). Regulation of the DNA Repair Complex during Somatic Hypermutation and Class-Switch Recombination. Journal of Immunology, 200(12), 4146-4156
Open this publication in new window or tab >>Regulation of the DNA Repair Complex during Somatic Hypermutation and Class-Switch Recombination
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2018 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 200, no 12, p. 4146-4156Article in journal (Refereed) Published
Abstract [en]

B lymphocytes optimize Ab responses by somatic hypermutation (SH), which introduces pointmutations in the variable regions of the Ab genes and by class-switch recombination (CSR), which changes the expressed C region exon of the IgH. These Ab diversification processes are initiated by the deaminating enzyme activation-induced cytidine deaminase followed by many DNA repair enzymes, ultimately leading to deletions and a high mutation rate in the Ab genes, whereas DNA lesions made by activation-induced cytidine deaminase are repaired with low error rate on most other genes. This indicates an advanced regulation of DNA repair. In this study, we show that initiation of Ab diversification in B lymphocytes of mouse spleen leads to formation of a complex between many proteins in DNA repair. We show also thatBCR activation, which signals the end of successful SH, reduces interactions between some proteins in the complex and increases other interactions in the complex with varying kinetics. Furthermore, we show increased localization of SH-and CSR-coupled proteins on switch regions of the Igh locus upon initiation of SH/CSR and differential changes in the localization upon BCR signaling, which terminates SH. These findings provide early evidence for a DNA repair complex or complexes that may be of functional significance for carrying out essential roles in SH and/or CSR in B cells.

Place, publisher, year, edition, pages
American Association of Immunologists, 2018
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-151570 (URN)10.4049/jimmunol.1701586 (DOI)000442386300029 ()29728513 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2018-09-10 Created: 2018-09-10 Last updated: 2018-09-10Bibliographically approved
Hauser, J., Grundström, C., Kumar, R. & Grundström, T. (2016). Regulated localization of an AID complex with E2A, PAX5 and IRF4 at the Igh locus. Molecular Immunology, 80, 78-90
Open this publication in new window or tab >>Regulated localization of an AID complex with E2A, PAX5 and IRF4 at the Igh locus
2016 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 80, p. 78-90Article in journal (Refereed) Published
Abstract [en]

Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates somatic hypermutation (SH) and class switch recombination (CSR) by deaminating cytosine to uracil. The targeting of AID and therefore SH and CSR to Ig genes is a central process of the immune system, but the trans-acting factors mediating the specific targeting have remained elusive. Here we show that defective calmodulin inhibition of the transcription factor E2A after activation of the B cell receptor (BCR) leads to reduced BCR, IL4 plus CD40 ligand stimulated CSR to IgE and instead CSR to other Ig classes. AID that initiates CSR is shown to be in a complex with the transcription factors E2A, PAX5 and IRF4 on key sequences of the Igh locus. Calmodulin shows proximity with each of them after BCR stimulation. BCR signaling reduces binding of the proteins to some of the target sites on the Igh locus, and calmodulin resistance of E2A blocks these reductions. AID binds directly to the bHLH domain of E2A and to the PD domain of PAX5. E2A, AID, PAX5 and IRF4 are components of a CSR complex that is redistributed on the Igh locus by BCR signaling through calmodulin binding.

Keywords
Class switch recombination, Antibodies, Activation-induced cytidine deaminase, Transcription factors, E2A, Calmodulin
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-130546 (URN)10.1016/j.molimm.2016.10.014 (DOI)000395847100010 ()2-s2.0-84994651161 (Scopus ID)
Available from: 2017-01-23 Created: 2017-01-23 Last updated: 2018-06-09Bibliographically approved
Grundström, T., Hauser, J., Grundström, C., Kumar, A., Priya, A. & Kumar, R. (2016). Regulation of diversification and affinity maturation of antibodies. International Journal of Molecular Medicine, 38, S43-S43
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2016 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 38, p. S43-S43Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Spandidos, 2016
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-126770 (URN)000383733000154 ()
Note

Supplement: 1, Meeting Abstract: 253

Available from: 2016-10-18 Created: 2016-10-13 Last updated: 2018-06-09Bibliographically approved
Grundström, T., Hauser, J., Grundström, C., Kumar, R. & Ahmed, T. (2015). Mechanisms controlling diversification and affinity maturation of antibodies. International Journal of Molecular Medicine, 36, S43-S43
Open this publication in new window or tab >>Mechanisms controlling diversification and affinity maturation of antibodies
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2015 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 36, p. S43-S43Article in journal, Meeting abstract (Other academic) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-110605 (URN)000361863000157 ()
Note

Supplement: 1 Meeting Abstract: 256

Available from: 2015-10-28 Created: 2015-10-23 Last updated: 2018-06-07Bibliographically approved
Hauser, J., Grundström, C., Kumar, R. & Grundström, T. (2015). Signal regulated localisation of a mutagenic protein complex at the Igh locus. Paper presented at 40th Congress of the Federation-of-European-Biochemical-Societies (FEBS) - The Biochemical Basis of Life, Berlin, July 4-9, 2015. The FEBS Journal, 282, 13-13
Open this publication in new window or tab >>Signal regulated localisation of a mutagenic protein complex at the Igh locus
2015 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 282, p. 13-13Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Our system to produce antibodies is critical for our survival against numerous infections, but it causes also many tumors. B-lymphocytes can modify their immunoglobulin (Ig) genes to generate specific antibodies with a new isotype and enhanced affinity against an antigen. Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates these processes by deaminating cytosine to uracil. How somatic hypermutation (SH) and class switch recombination (CSR) are targeted is key to understanding the defect DNA integrity in lymphomas and also in other tumors where inflammatory signals aberrantly induces AID. The trans-acting factors mediating specific targeting of AID and thereby SH and CSR have remained elusive. Here we show that mutant E2A with defect inhibition by the Ca2+sensor protein calmodulin results in reduced B cell receptor- (BCR-), IL4-plus CD40 ligand-stimulated CSR to IgE and instead aberrant CSR. AID is shown to be together with the transcription factors E2A, PAX5 and IRF4 in a complex on key sequences of the Igh locus in activated mouse splenic B cells. Calmodulin shows proximity with each of them after BCR stimulation. Direct protein-protein interactions enable formation of the complexes. BCR signaling reduces binding of the proteins to some of the target sites on the Igh locus, and calmodulin resistance of E2A blocks reduction of binding to these target sites and increases binding to other target sites. Thus, E2A, AID, PAX5 and IRF4 are components of a CSR and SH complex that is redistributed on the IgH gene by BCR signaling through calmodulin binding.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2015
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-111161 (URN)10.1111/febs.13320 (DOI)000362570600032 ()
Conference
40th Congress of the Federation-of-European-Biochemical-Societies (FEBS) - The Biochemical Basis of Life, Berlin, July 4-9, 2015
Note

Supplement: 1

Special Issue: SI

Meeting Abstract: P02-003-SH

Available from: 2015-11-10 Created: 2015-11-06 Last updated: 2018-06-07Bibliographically approved
Hauser, J., Grundström, C. & Grundström, T. (2014). Allelic Exclusion of IgH through Inhibition of E2A in a VDJ Recombination Complex. Journal of Immunology, 192(5), 2460-2470
Open this publication in new window or tab >>Allelic Exclusion of IgH through Inhibition of E2A in a VDJ Recombination Complex
2014 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 192, no 5, p. 2460-2470Article in journal (Refereed) Published
Abstract [en]

A key feature of the immune system is the paradigm that one lymphocyte has only one Ag specificity that can be selected for or against. This requires that only one of the alleles of genes for AgR chains is made functional. However, the molecular mechanism of this allelic exclusion has been an enigma. In this study, we show that B lymphocytes with E2A that cannot be inhibited by calmodulin are dramatically defective in allelic exclusion of the IgH locus. Furthermore, we provide data supporting that E2A, PAX5, and the RAGs are in a VDJ recombination complex bound to key sequences on the Igh gene. We show that pre-BCR activation releases the VDJ recombination complex through calmodulin binding to E2A. We also show that pre-BCR signaling downregulates several components of the recombination machinery, including RAG1, RAG2, and PAX5, through calmodulin inhibition of E2A.

Place, publisher, year, edition, pages
Bethesda: American Association of Immunologists, 2014
National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-87877 (URN)10.4049/jimmunol.1302216 (DOI)000332701400050 ()24470503 (PubMedID)
Available from: 2014-04-14 Created: 2014-04-14 Last updated: 2018-06-08Bibliographically approved
Hauser, J., Kumar, R., Wallenius, A., Grundström, C., Ahmed, T. & Grundström, T. (2014). Regulation of diversification and affinity maturation of antibodies. International Journal of Molecular Medicine, 34, S50-S50
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2014 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 34, p. S50-S50Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Spandidos publishing, 2014
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-94174 (URN)000341276000184 ()
Note

Supplement 1, Meeting abstract 283

Available from: 2014-10-06 Created: 2014-10-06 Last updated: 2018-06-07Bibliographically approved
Hauser, J., Verma-Gaur, J., Wallenius, A., Grundström, C. & Grundström, T. (2013). Mechanisms controlling diversification and affinity maturation of antibodies. International Journal of Molecular Medicine, 32, S45-S45
Open this publication in new window or tab >>Mechanisms controlling diversification and affinity maturation of antibodies
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2013 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 32, p. S45-S45Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-81844 (URN)000324507400162 ()
Available from: 2013-10-22 Created: 2013-10-22 Last updated: 2018-06-08Bibliographically approved
Oruganti, S. R., Edin, S., Grundström, C. & Grundström, T. (2011). CaMKII targets Bc110 in T-cell receptor induced activation of NF-κB. Molecular Immunology, 48(12-13), 1448-1460
Open this publication in new window or tab >>CaMKII targets Bc110 in T-cell receptor induced activation of NF-κB
2011 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 48, no 12-13, p. 1448-1460Article in journal (Refereed) Published
Abstract [en]

Recognition of antigen by T- or B-cell receptors leads to formation of an immunological synapse and initiation of signalling events that collaborate to determine the nature of the adaptive immune response. Activation of NF-κB transcription factors has a key role in regulation of numerous genes with important functions in immune responses and inflammation and is of great importance for lymphocyte activation and differentiation. The activation of NF-κB depends on changes in intracellular Ca2+ levels, and both calmodulin (CaM) and a CaM-dependent kinase, CaMKII, help regulate NF-κB activation after T-cell receptor (TCR) stimulation, but the mechanisms are not well characterized. Here we have analyzed the functional role of CaMKII in the signalling pathway from the TCR to activation of IKK, the kinase that phosphorylates the NF-κB inhibitor IκB. We show that CaMKII is recruited to the immunological synapse where it interacts with and phosphorylates the signalling adaptor protein Bcl10. Furthermore, phosphorylation of the CARD domain of Bcl10 by CaMKII regulates the interactions within the important Carma1, Bcl10, Malt1 signalling complex and the essential signal induced ubiquitinations of Bcl10 and IKKγ. We propose a novel mechanism whereby Ca2+ signals can be integrated at the immunological synapse through CaMKII-dependent phosphorylation of Bcl10.

Place, publisher, year, edition, pages
Elsevier, 2011
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-3572 (URN)10.1016/j.molimm.2011.03.020 (DOI)
Available from: 2008-10-29 Created: 2008-10-29 Last updated: 2018-06-09Bibliographically approved
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