Ap4A Regulates Directional Mobility and Antigen Presentation in Dendritic Cells

Shu, Shin La; Paruchuru, Lakshmi Bhargavi; Tay, Neil Q.; Chua, Yen Leong; Foo, Adeline Shen Yun; Yang, Chris; Liong, Ka Hang; Koh, Esther G. L.; Lee, Angeline; Nechushtan, Hovav; Razin, Ehud; Kemeny, David M.

doi:10.1016/j.isci.2019.05.045

Cited by 6 publications

(6 citation statements)

References 35 publications

(39 reference statements)

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“…regulation of AP 4 A synthesis has been shown to increase motility and antigen presentation functions of dendritic cells. As expected, BMDC from Nudt2 fl/fl /CD11c-cre mice in which AP 4 A synthesis is enhanced due to the absence of Ap4A hydrolase prime a significantly stronger CD8 + T-cell responses highlighting the role of LysRS in regulating not only motility and antigen presentation, but functional activation of T cells as well (47). The roles of other subunits of the mARS complex in regard to DC function however remain elusive and therefore future studies will be critical to advance our understanding of this area.…”

Section: Dendritic Cellssupporting

confidence: 79%

The mARS complex: a critical mediator of immune regulation and homeostasis

Amanya,

Oyewole-Said,

Ernste

et al. 2024

Front. Immunol.

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Over the course of evolution, many proteins have undergone adaptive structural changes to meet the increasing homeostatic regulatory demands of multicellularity. Aminoacyl tRNA synthetases (aaRS), enzymes that catalyze the attachment of each amino acid to its cognate tRNA, are such proteins that have acquired new domains and motifs that enable non-canonical functions. Through these new domains and motifs, aaRS can assemble into large, multi-subunit complexes that enhance the efficiency of many biological functions. Moreover, because the complexity of multi-aminoacyl tRNA synthetase (mARS) complexes increases with the corresponding complexity of higher eukaryotes, a contribution to regulation of homeostatic functions in multicellular organisms is hypothesized. While mARS complexes in lower eukaryotes may enhance efficiency of aminoacylation, little evidence exists to support a similar role in chordates or other higher eukaryotes. Rather, mARS complexes are reported to regulate multiple and variegated cellular processes that include angiogenesis, apoptosis, inflammation, anaphylaxis, and metabolism. Because all such processes are critical components of immune homeostasis, it is important to understand the role of mARS complexes in immune regulation. Here we provide a conceptual analysis of the current understanding of mARS complex dynamics and emerging mARS complex roles in immune regulation, the increased understanding of which should reveal therapeutic targets in immunity and immune-mediated disease.

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Section: Dendritic Cellssupporting

confidence: 79%

The mARS complex: a critical mediator of immune regulation and homeostasis

Amanya,

Oyewole-Said,

Ernste

et al. 2024

Front. Immunol.

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“…Dendritic cells, the most potent APCs, express MITF. An interaction between MITF and the lysyl-tRNA synthetase (KARS1) has been reported to stimulate MITF transcriptional activity through the generation of diadenosine tetraphosphate (Ap4A), which is also a key regulator of antigen presentation [ 129 ]. Thus, MITF can influence the initiation and maintenance of primary immune responses.…”

Section: Roles Of Mitf In Nonmelanoma Cellsmentioning

confidence: 99%

The complex relationship between MITF and the immune system: a Melanoma ImmunoTherapy (response) Factor?

2020

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The clinical benefit of immune checkpoint inhibitory therapy (ICT) in advanced melanomas is limited by primary and acquired resistance. The molecular determinants of the resistance have been extensively studied, but these discoveries have not yet been translated into therapeutic benefits. As such, a paradigm shift in melanoma treatment, to surmount the therapeutic impasses linked to the resistance, is an important ongoing challenge.This review outlines the multifaceted interplay between microphthalmia-associated transcription factor (MITF), a major determinant of the biology of melanoma cells, and the immune system. In melanomas, MITF functions downstream oncogenic pathways and microenvironment stimuli that restrain the immune responses. We highlight how MITF, by controlling differentiation and genome integrity, may regulate melanoma-specific antigen expression by interfering with the endolysosomal pathway, KARS1, and antigen processing and presentation. MITF also modulates the expression of coinhibitory receptors, i.e., PD-L1 and HVEM, and the production of an inflammatory secretome, which directly affects the infiltration and/or activation of the immune cells.Furthermore, MITF is also a key determinant of melanoma cell plasticity and tumor heterogeneity, which are undoubtedly one of the major hurdles for an effective immunotherapy. Finally, we briefly discuss the role of MITF in kidney cancer, where it also plays a key role, and in immune cells, establishing MITF as a central mediator in the regulation of immune responses in melanoma and other cancers.We propose that a better understanding of MITF and immune system intersections could help in the tailoring of current ICT in melanomas and pave the way for clinical benefits and long-lasting responses.

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“…To prevent deregulation of MITFtarget genes, levels of Ap 4 A are subsequently down-regulated by hydrolysis, demonstrated by the changes in expression of rat MITF-(and USF2-) target genes when Nudt2, the major Ap 4 A hydrolase, is knocked down (Carmi-Levy et al, 2008). Similarly, MITF localization to the nucleus and increased transcription of MITF-target gene TRACP5 has also been demonstrated in murine dendritic cells that have a floxed Nudt2 gene and therefore a 30-fold increase in Ap 4 A levels (La Shu et al, 2019). Further evidence for the importance of precise control of Ap 4 A levels was demonstrated in bone marrow-derived dendritic cells (BMDCs) with floxed NUDT2.…”

Section: Ap 4 A-mediated Regulation Of Gene Expression In Eukaryotesmentioning

confidence: 99%

“…Further evidence for the importance of precise control of Ap 4 A levels was demonstrated in bone marrow-derived dendritic cells (BMDCs) with floxed NUDT2 . This leads to greater motility and increased proliferation of CD8+ T cells that require cross-antigen presentation, however, this only correlates with increased MITF target gene expression and is not necessarily directly caused by it ( La Shu et al, 2019 ). The structural, biochemical and cellular analysis of the role of Ap 4 A in the regulation of HINT1-MITF demonstrate that Ap 4 A does indeed perform a bona fide signaling role that can precisely regulate transcriptional programs in specific cellular lineages.…”

Section: Introductionmentioning

confidence: 99%

Re-evaluation of Diadenosine Tetraphosphate (Ap4A) From a Stress Metabolite to Bona Fide Secondary Messenger

Ferguson

McLennan

Urbaniak

et al. 2020

Front. Mol. Biosci.

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Cellular homeostasis requires adaption to environmental stress. In response to various environmental and genotoxic stresses, all cells produce dinucleoside polyphosphates (Np n Ns), the best studied of which is diadenosine tetraphosphate (Ap 4 A). Despite intensive investigation, the precise biological roles of these molecules have remained elusive. However, recent studies have elucidated distinct and specific signaling mechanisms for these nucleotides in prokaryotes and eukaryotes. This review summarizes these key discoveries and describes the mechanisms of Ap 4 A and Ap 4 N synthesis, the mediators of the cellular responses to increased intracellular levels of these molecules and the hydrolytic mechanisms required to maintain low levels in the absence of stress. The intracellular responses to dinucleotide accumulation are evaluated in the context of the “friend” and “foe” scenarios. The “friend (or alarmone) hypothesis” suggests that Ap n N act as bona fide secondary messengers mediating responses to stress. In contrast, the “foe” hypothesis proposes that Ap n N and other Np n N are produced by non-canonical enzymatic synthesis as a result of physiological and environmental stress in critically damaged cells but do not actively regulate mitigating signaling pathways. In addition, we will discuss potential target proteins, and critically assess new evidence supporting roles for Ap n N in the regulation of gene expression, immune responses, DNA replication and DNA repair. The recent advances in the field have generated great interest as they have for the first time revealed some of the molecular mechanisms that mediate cellular responses to Ap n N. Finally, areas for future research are discussed with possible but unproven roles for intracellular Ap n N to encourage further research into the signaling networks that are regulated by these nucleotides.

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Ap4A Regulates Directional Mobility and Antigen Presentation in Dendritic Cells

Cited by 6 publications

References 35 publications

The mARS complex: a critical mediator of immune regulation and homeostasis

The mARS complex: a critical mediator of immune regulation and homeostasis

The complex relationship between MITF and the immune system: a Melanoma ImmunoTherapy (response) Factor?

Re-evaluation of Diadenosine Tetraphosphate (Ap4A) From a Stress Metabolite to Bona Fide Secondary Messenger

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