Post-transcriptional Gene Regulation in T Cells – AG Vigo Heissmeyer

Deregulation or inactivation of selected RNA-binding proteins induces the development of autoimmune and autoinflammatory diseases or boosts anti-tumor responses, respectively. We are trying to understand the complex interactions of selected RNA-binding proteins with newly identified cooperation partners and dissect how this network functions to control target mRNA expression via composite cis-elements. We aim to identify novel targets and markers and possible modes of therapeutic intervention. To reach this goal we undertake mechanistic analyses addressing the structural basis, function or regulation and employ global approaches to define binding sites and interactomes. We assess the physiologic importance of identified regulators in genetic models studying immune homeostasis, induced immune responses and pathologies.

Selected publications:

Tavernier, S. J. et al. A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation. Nat Commun 10, 5337, https://doi.org/10.1038/s41467-019-12704-6 (2019).

Essig, K. et al. Roquin targets mRNAs in a 3'-UTR-specific manner by different modes of regulation. Nat Commun 9, 3810, doi:10.1038/s41467-018-06184-3 (2018).

Jeltsch, K. M. et al. Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation. Nat Immunol 15, 1079-1089, doi:10.1038/ni.3008 (2014).

Vogel, K. U. et al. Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation. Immunity 38, 655-668, doi:10.1016/j.immuni.2012.12.004 (2013).

We study structure-function and regulation of selected RNA-binding proteins, endoribonucleases, exoribonucleases, miRNAs, components of the m6A methyltransferase complex as well as their cofactors and downstream effectors. We define the transcriptome-interacting proteome (RBPome) and ask which proteins are in close proximity in T cells and cooperate functionally to control specific mRNA targets. Ongoing work of our group describes m6A methylation of RNA as well as the interaction of RNA-binding proteins with the transcriptome at near-nucleotide resolution in T cells. These studies will provide a detailed understanding of the post-transcriptional drivers and their molecular interactions in T cells and enable future therapeutic modulation of T cell function in autoimmune or autoinflammatory diseases as well as anti-tumor responses.

These aspects of our work receive funding from the DFG (Projects 444891219, 432656284, 313381103).

Selected publications:

Hoefig, K.P., Reim, A., Gallus, C. et al. Defining the RBPome of primary T helper cells to elucidate higher-order Roquin-mediated mRNA regulation. Nat Commun 12, 5208 (2021). https://doi.org/10.1038/s41467-021-25345-5

Essig, K. et al. Roquin targets mRNAs in a 3'-UTR-specific manner by different modes of regulation. Nat Commun 9, 3810, doi:10.1038/s41467-018-06184-3 (2018).

Rehage, N. et al. Binding of NUFIP2 to Roquin promotes recognition and regulation of ICOS mRNA. Nat Commun 9, 299, doi:10.1038/s41467-017-02582-1 (2018).

Janowski, R. et al. Roquin recognizes a non-canonical hexaloop structure in the 3'-UTR of Ox40. Nat Commun 7, 11032, doi:10.1038/ncomms11032 (2016).

Warth, S. C. et al. Induced miR-99a expression represses Mtor cooperatively with miR-150 to promote regulatory T-cell differentiation. EMBO J 34, 1195-1213, doi:10.15252/embj.201489589 (2015).

Schlundt, A. et al. Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation. Nat Struct Mol Biol 21, 671-678, doi:10.1038/nsmb.2855 (2014).

Jeltsch, K. M. et al. Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation. Nat Immunol 15, 1079-1089, doi:10.1038/ni.3008 (2014).

Hoefig, K. P. et al. Eri1 degrades the stem-loop of oligouridylated histone mRNAs to induce replication-dependent decay. Nat Struct Mol Biol 20, 73-81, doi:10.1038/nsmb.2450 (2013).

Glasmacher, E. et al. Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression. Nat Immunol 11, 725-733, doi:10.1038/ni.1902 (2010).

Ansel, K. M. et al. Mouse Eri1 interacts with the ribosome and catalyzes 5.8S rRNA processing. Nat Struct Mol Biol 15, 523-530, doi:10.1038/nsmb.1417 (2008).

We study post-transcriptional gene regulation during development, homeostasis and in adaptive immune responses. Specifically, we address how these molecular programs impact on T cell activation, metabolic programs, differentiation, apoptosis, survival and effector functions. Projects of our lab ask how T cells with dysregulation or loss-of-function of specific RBPs drive autoimmunity, induce tissue inflammation or neoplasia. Conversely, we investigate how the system can be used to harness T cells in anti-tumor responses.
Our mission is to connect the molecular mechanisms with T cell phenotypes and pathologies to enable future therapeutic intervention.

These aspects of our work receive funding from the DFG (Project 210592381) and Deutsche Krebshilfe (70113538).

Selected publications:

Tavernier, S. J. et al. Author Correction: A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation. Nat Commun 10, 5337, doi:10.1038/s41467-019-13379-9 (2019).

Essig, K. et al. Roquin targets mRNAs in a 3'-UTR-specific manner by different modes of regulation. Nat Commun 9, 3810, doi:10.1038/s41467-018-06184-3 (2018).

Jeltsch, K. M. et al. Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation. Nat Immunol 15, 1079-1089, doi:10.1038/ni.3008 (2014).

Vogel, K. U. et al. Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation. Immunity 38, 655-668, doi:10.1016/j.immuni.2012.12.004 (2013).

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DFG: SFB 1054 Control and Plasticity of Cell-Fate Decisions in the Immune System
Project A03: Post-transcriptional Control of T Cell Activation and Differentiation

Wilhelm Sander Stiftung: Inhibition der Roquin-Aktivität zur Verbesserung adoptiver T-Zelltherapie

Deutsche Krebshilfe: Investigation of Roquin function in the prevention of pancreas inflammation and neoplasia

HE 3359/7-1 DFG/SNF: RNA-binding proteins and control of mRNA metabolism in th regulation of adaptive immunity in humans

HE3359/8-1 DFG: Investigating the role of accessory proteins of the methytransferase complex and the importance of m6A mRNA modification in T cells

HE 3359/5-2 DFG SPP1935: Differential protein- and RNA-interactions of Roquin specify alternative modes of post-transcriptional gene regulation