Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses.
Animals
Autoimmunity
Cytotoxicity, Immunologic
Female
HEK293 Cells
HeLa Cells
Humans
Immunity, Humoral
Immunotherapy, Adoptive
Male
Melanoma, Experimental
/ genetics
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Phenotype
Protein Binding
Repressor Proteins
/ genetics
Ribonucleases
/ genetics
Skin Neoplasms
/ genetics
T-Lymphocytes
/ immunology
Tumor Microenvironment
Ubiquitin-Protein Ligases
/ genetics
Journal
Nature immunology
ISSN: 1529-2916
Titre abrégé: Nat Immunol
Pays: United States
ID NLM: 100941354
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
29
06
2020
accepted:
30
09
2021
pubmed:
24
11
2021
medline:
30
12
2021
entrez:
23
11
2021
Statut:
ppublish
Résumé
Roquin and Regnase-1 proteins bind and post-transcriptionally regulate proinflammatory target messenger RNAs to maintain immune homeostasis. Either the sanroque mutation in Roquin-1 or loss of Regnase-1 cause systemic lupus erythematosus-like phenotypes. Analyzing mice with T cells that lack expression of Roquin-1, its paralog Roquin-2 and Regnase-1 proteins, we detect overlapping or unique phenotypes by comparing individual and combined inactivation. These comprised spontaneous activation, metabolic reprogramming and persistence of T cells leading to autoimmunity. Here, we define an interaction surface in Roquin-1 for binding to Regnase-1 that included the sanroque residue. Mutations in Roquin-1 impairing this interaction and cooperative regulation of targets induced T follicular helper cells, germinal center B cells and autoantibody formation. These mutations also improved the functionality of tumor-specific T cells by promoting their accumulation in the tumor and reducing expression of exhaustion markers. Our data reveal the physical interaction of Roquin-1 with Regnase-1 as a hub to control self-reactivity and effector functions in immune cell therapies.
Identifiants
pubmed: 34811541
doi: 10.1038/s41590-021-01064-3
pii: 10.1038/s41590-021-01064-3
pmc: PMC8996344
mid: NIHMS1779511
doi:
Substances chimiques
Repressor Proteins
0
roquin-2 protein, mouse
0
Rc3h1 protein, mouse
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Ribonucleases
EC 3.1.-
Zc3h12a protein, mouse
EC 3.1.-
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1563-1576Subventions
Organisme : NIAID NIH HHS
ID : R15 AI138116
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Pratama, A. et al. Roquin-2 shares functions with its paralog Roquin-1 in the repression of mRNAs controlling T follicular helper cells and systemic inflammation. Immunity 38, 669–680 (2013).
pubmed: 23583642
doi: 10.1016/j.immuni.2013.01.011
Tavernier, S. J. et al. A human immune dysregulation syndrome characterized by severe hyperinflammation with a homozygous nonsense Roquin-1 mutation. Nat. Commun. 10, 4779 (2019).
pubmed: 31636267
pmcid: 6803705
doi: 10.1038/s41467-019-12704-6
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 (2013).
pubmed: 23583643
doi: 10.1016/j.immuni.2012.12.004
Matsushita, K. et al. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 458, 1185–1190 (2009).
pubmed: 19322177
doi: 10.1038/nature07924
Uehata, T. et al. Malt1-induced cleavage of regnase-1 in CD4
Jeltsch, K. M. et al. Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(
pubmed: 25282160
doi: 10.1038/ni.3008
Mino, T. et al. Regnase-1 and Roquin regulate a common element in inflammatory mRNAs by spatiotemporally distinct mechanisms. Cell 161, 1058–1073 (2015).
pubmed: 26000482
doi: 10.1016/j.cell.2015.04.029
Jeltsch, K. M. & Heissmeyer, V. Regulation of T cell signaling and autoimmunity by RNA-binding proteins. Curr. Opin. Immunol. 39, 127–135 (2016).
pubmed: 26871597
doi: 10.1016/j.coi.2016.01.011
Leppek, K. et al. Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs. Cell 153, 869–881 (2013).
pubmed: 23663784
doi: 10.1016/j.cell.2013.04.016
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 (2010).
pubmed: 20639877
doi: 10.1038/ni.1902
Sgromo, A. et al. A CAF40-binding motif facilitates recruitment of the CCR4-NOT complex to mRNAs targeted by Drosophila Roquin. Nat. Commun. 8, 14307 (2017).
pubmed: 28165457
pmcid: 5303829
doi: 10.1038/ncomms14307
Mino, T. et al. Translation-dependent unwinding of stem-loops by UPF1 licenses Regnase-1 to degrade inflammatory mRNAs. Nucleic Acids Res. 47, 8838–8859 (2019).
pubmed: 31329944
pmcid: 7145602
Fu, M. & Blackshear, P. J. RNA-binding proteins in immune regulation: a focus on CCCH zinc finger proteins. Nat. Rev. Immunol. 17, 130–143 (2017).
pubmed: 27990022
doi: 10.1038/nri.2016.129
Vinuesa, C. G. et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452–458 (2005).
pubmed: 15917799
doi: 10.1038/nature03555
Akira, S. Regnase-1, a ribonuclease involved in the regulation of immune responses. Cold Spring Harb. Symp. Quant. Biol. 78, 51–60 (2013).
pubmed: 24163394
doi: 10.1101/sqb.2013.78.019877
Heissmeyer, V. & Vogel, K. U. Molecular control of T
pubmed: 23550652
doi: 10.1111/imr.12056
von Gamm, M. et al. Immune homeostasis and regulation of the interferon pathway require myeloid-derived Regnase-3. J. Exp. Med. 216, 1700–1723 (2019).
doi: 10.1084/jem.20181762
Wei, J. et al. Targeting Regnase-1 programs long-lived effector T cells for cancer therapy. Nature 576, 471–476 (2019).
pubmed: 31827283
pmcid: 6937596
doi: 10.1038/s41586-019-1821-z
Zheng, W. et al. Regnase-1 suppresses TCF-1
pubmed: 33690816
doi: 10.1182/blood.2020009309
Li, Y. et al. Central role of myeloid MCPIP1 in protecting against LPS-induced inflammation and lung injury. Signal Transduct. Target Ther. 2, 17066 (2017).
pubmed: 29263935
pmcid: 5721545
doi: 10.1038/sigtrans.2017.66
Bertossi, A. et al. Loss of Roquin induces early death and immune deregulation but not autoimmunity. J. Exp. Med. 208, 1749–1756 (2011).
pubmed: 21844204
pmcid: 3171092
doi: 10.1084/jem.20110578
Cui, X. et al. Regnase-1 and Roquin nonredundantly regulate T
pubmed: 29127149
doi: 10.4049/jimmunol.1701211
Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007).
pubmed: 17251932
doi: 10.1038/nature05541
Sledzinska, A. TGF-β signalling is required for CD4
pubmed: 24115907
pmcid: 3792861
doi: 10.1371/journal.pbio.1001674
Zeitrag, J., Alterauge, D., Dahlstrom, F. & Baumjohann, D. Gene dose matters: considerations for the use of inducible CD4-CreER(T2) mouse lines. Eur. J. Immunol. 50, 603–605 (2020).
pubmed: 32087088
doi: 10.1002/eji.201948461
Hudson, W. H. et al. Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1
pubmed: 31810882
pmcid: 6920571
doi: 10.1016/j.immuni.2019.11.002
McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev. Immunol. 37, 457–495 (2019).
pubmed: 30676822
doi: 10.1146/annurev-immunol-041015-055318
Yu, D. et al. Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450, 299–303 (2007).
pubmed: 18172933
doi: 10.1038/nature06253
Tan, A. H., Wong, S. C. & Lam, K. P. Regulation of mouse inducible costimulator (ICOS) expression by Fyn-NFATc2 and ERK signaling in T cells. J. Biol. Chem. 281, 28666–28678 (2006).
pubmed: 16880206
doi: 10.1074/jbc.M604081200
Iwasaki, H. et al. The IκB kinase complex regulates the stability of cytokine-encoding mRNA induced by TLR-IL-1R by controlling degradation of regnase-1. Nat. Immunol. 12, 1167–1175 (2011).
pubmed: 22037600
doi: 10.1038/ni.2137
Janowski, R. et al. Roquin recognizes a non-canonical hexaloop structure in the 3′-UTR of Ox40. Nat. Commun. 7, 11032 (2016).
pubmed: 27010430
pmcid: 5603727
doi: 10.1038/ncomms11032
Schlundt, A. et al. Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation. Nat. Struct. Mol. Biol. 21, 671–678 (2014).
pubmed: 25026077
doi: 10.1038/nsmb.2855
Srivastava, M. et al. Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis. Nat. Commun. 6, 6253 (2015).
pubmed: 25697406
doi: 10.1038/ncomms7253
Tan, D., Zhou, M., Kiledjian, M. & Tong, L. The ROQ domain of Roquin recognizes mRNA constitutive-decay element and double-stranded RNA. Nat. Struct. Mol. Biol. 21, 679–685 (2014).
pubmed: 25026078
pmcid: 4125485
doi: 10.1038/nsmb.2857
Suzuki, H. I. et al. MCPIP1 ribonuclease antagonizes dicer and terminates microRNA biogenesis through precursor microRNA degradation. Mol. Cell 44, 424–436 (2011).
pubmed: 22055188
doi: 10.1016/j.molcel.2011.09.012
Lee, S. K. et al. Interferon-γ excess leads to pathogenic accumulation of follicular helper T cells and germinal centers. Immunity 37, 880–892 (2012).
pubmed: 23159227
doi: 10.1016/j.immuni.2012.10.010
Ellyard, J. I. et al. Heterozygosity for Roquinsan leads to angioimmunoblastic T-cell lymphoma-like tumors in mice. Blood 120, 812–821 (2012).
pubmed: 22700722
doi: 10.1182/blood-2011-07-365130
Blank, C. U. et al. Defining ‘T cell exhaustion’. Nat. Rev. Immunol. 19, 665–674 (2019).
pubmed: 31570879
pmcid: 7286441
doi: 10.1038/s41577-019-0221-9
Essig, K. et al. Roquin targets mRNAs in a 3′-UTR-specific manner by different modes of regulation. Nat. Commun. 9, 3810 (2018).
pubmed: 30232334
pmcid: 6145892
doi: 10.1038/s41467-018-06184-3
Murakawa, Y. et al. RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κB pathway. Nat. Commun. 6, 7367 (2015).
pubmed: 26170170
doi: 10.1038/ncomms8367
Song, J. et al. Human cytomegalovirus induces and exploits Roquin to counteract the IRF1-mediated antiviral state. Proc. Natl Acad. Sci. USA 116, 18619–18628 (2019).
pubmed: 31451648
pmcid: 6744924
doi: 10.1073/pnas.1909314116
Essig, K. et al. Roquin suppresses the PI3K-mTOR signaling pathway to inhibit T helper cell differentiation and conversion of T
pubmed: 29246441
doi: 10.1016/j.immuni.2017.11.008
Nagahama, Y. et al. Regnase-1 controls colon epithelial regeneration via regulation of mTOR and purine metabolism. Proc. Natl Acad. Sci. USA 115, 11036–11041 (2018).
pubmed: 30297433
pmcid: 6205455
doi: 10.1073/pnas.1809575115
Hoefig, K. P. et al. Defining the RBPome of primary T helper cells to elucidate higher-order Roquin-mediated mRNA regulation. Nat. Commun. 12, 5208 (2021).
pubmed: 34471108
pmcid: 8410761
doi: 10.1038/s41467-021-25345-5
Lee, P. P. et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15, 763–774 (2001).
pubmed: 11728338
doi: 10.1016/S1074-7613(01)00227-8
Hogquist, K. A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).
pubmed: 8287475
doi: 10.1016/0092-8674(94)90169-4
Hochedlinger, K., Yamada, Y., Beard, C. & Jaenisch, R. Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121, 465–477 (2005).
pubmed: 15882627
doi: 10.1016/j.cell.2005.02.018
Schieweck, R. et al. Pumilio2 and Staufen2 selectively balance the synaptic proteome. Cell Rep. 35, 109279 (2021).
pubmed: 34161769
doi: 10.1016/j.celrep.2021.109279
Digman, M. A., Caiolfa, V. R., Zamai, M. & Gratton, E. The phasor approach to fluorescence lifetime imaging analysis. Biophys. J. 94, L14–L16 (2008).
pubmed: 17981902
doi: 10.1529/biophysj.107.120154