Importin Beta Plays an Essential Role in the Regulation of the LysRS-Ap<sub>4</sub>A Pathway in Immunologically Activated Mast Cells

Carmi-Levy, Irit; Motzik, Alex; Ofir-Birin, Yifat; Yagil, Zohar; Yang, Christopher Maolin; Kemeny, David M.; Han, Jung Min; Kim, Sung Hoon; Kay, Gillian; Nechushtan, Hovav; Suzuki, Ryo; Rivera, Juan; Razin, Ehud

doi:10.1128/mcb.01159-10

Cited by 17 publications

(18 citation statements)

References 39 publications

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“…(iii) can a plant cell receptor be identified with specificity for these dinucleotides; (iv) do the exogenously applied diadenosine polyphosphates affect accumulation of particular phenylpropanoic compound(s) in the plant tissues; and (v) how do other genes and enzymes of the phenylpropanoid pathways respond to those uncommon (di)nucleotides? Based on existing knowledge of the reactions caused in cells by cadmium [12,13,[21][22][23] and on the observations communicated in this paper, we postulate that in plant cells Cd (II) causes accumulation of Ap 3 A and/or Ap 4 A and, by analogy with the activation of the MITF transcription factor in mast cells by Ap 4 A [44], these compounds interact with transcription factors that control mainly the PAL2 gene and to a lesser extent the 4CL genes. Since the metabolites of the phenylpropanoid pathways protect plants against the harmful effects of different types of stress, Ap 3 A and Ap 4 A behave in our biological system as true alarmones, initiating the rescue action.…”

Section: Discussionmentioning

confidence: 74%

“…Based on existing knowledge of the reactions caused in cells by cadmium [12,13,21–23] and on the observations communicated in this paper, we postulate that in plant cells Cd (II) causes accumulation of Ap 3 A and/or Ap 4 A and, by analogy with the activation of the MITF transcription factor in mast cells by Ap 4 A [44], these compounds interact with transcription factors that control mainly the PAL2 gene and to a lesser extent the 4CL genes. Since the metabolites of the phenylpropanoid pathways protect plants against the harmful effects of different types of stress, Ap 3 A and Ap 4 A behave in our biological system as true alarmones, initiating the rescue action.…”

Section: Discussionmentioning

confidence: 76%

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Diadenosine polyphosphates (Ap₃A and Ap₄A) behave as alarmones triggering the synthesis of enzymes of the phenylpropanoid pathway in Arabidopsis thaliana

Pietrowska‐Borek¹,

Nuc²,

Zielezińska³

et al. 2011

FEBS Open Bio

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It is known that cells under stress accumulate various dinucleoside polyphosphates, compounds suggested to function as alarmones. In plants, the phenylpropanoid pathways yield metabolites protecting these organisms against various types of stress. Observations reported in this communication link these two phenomena and provide an example of a metabolic “addressee” for an “alarm” signaled by diadenosine triphosphate (Ap3A) or diadenosine tetraphosphate (Ap4A). In response to added Ap3A or Ap4A, seedlings of Arabidopsis thaliana incubated in full nutrition medium increased both the expression of the genes for and the specific activity of phenylalanine ammonia-lyase and 4-coumarate:coenzyme A ligase, enzymes that control the beginning of the phenylpropanoid pathway. Neither adenine mononucleotides (AMP, ADP or ATP) nor adenosine evoked such effects. Reactions catalyzed in vitro by these enzymes were not affected by Ap3A or Ap4A.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 76%

Diadenosine polyphosphates (Ap₃A and Ap₄A) behave as alarmones triggering the synthesis of enzymes of the phenylpropanoid pathway in Arabidopsis thaliana

Pietrowska‐Borek¹,

Nuc²,

Zielezińska³

et al. 2011

FEBS Open Bio

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“…2D ). Interestingly, although conditional, membrane localization has been observed for human Ap4AH in mast cells 12 .…”

Section: Resultsmentioning

confidence: 99%

“…This is distinct from some plant-bacterial type hydrolases 8 9 11 . Eukaryotic Ap4AHs are predominantly cytoplasmic or nuclear, while the bacterial Ap4AHs appear to be ribosome associated 12 13 14 . Levels of Ap4A in a cell are largely regulated by the synthesis and hydrolysis dynamics of KRS (which synthesises ~80% cellular Ap4A) and Ap4A hydrolase 7 8 15 .…”

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confidence: 99%

Structural and functional attributes of malaria parasite diadenosine tetraphosphate hydrolase

Sharma

Yogavel

2016

Sci Rep

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Malaria symptoms are driven by periodic multiplication cycles of Plasmodium parasites in human red blood corpuscles (RBCs). Malaria infection still accounts for ~600,000 annual deaths, and hence discovery of both new drug targets and drugs remains vital. In the present study, we have investigated the malaria parasite enzyme diadenosine tetraphosphate (Ap4A) hydrolase that regulates levels of signalling molecules like Ap4A by hydrolyzing them to ATP and AMP. We have tracked the spatial distribution of parasitic Ap4A hydrolase in infected RBCs, and reveal its unusual localization on the infected RBC membrane in subpopulation of infected cells. Interestingly, enzyme activity assays reveal an interaction between Ap4A hydrolase and the parasite growth inhibitor suramin. We also present a high resolution crystal structure of Ap4A hydrolase in apo- and sulphate- bound state, where the sulphate resides in the enzyme active site by mimicking the phosphate of substrates like Ap4A. The unexpected infected erythrocyte localization of the parasitic Ap4A hydrolase hints at a possible role of this enzyme in purinerigic signaling. In addition, atomic structure of Ap4A hydrolase provides insights for selective drug targeting.

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“…For example, IgE stimulation of mast cells results in phosphorylation of LysRS on S207. LysRS is then released from the MSC and traffics to the nucleus (18,19), where it synthesizes a dinucleotide Ap4A, triggering transcriptional activation of several genes (20)(21)(22). In another example, following laminin receptor (67LR) stimulation of a variety of human cell lines, LysRS is phosphorylated on residue T52 by mitogen-activated protein kinase (MAPK), released from the MSC, and trafficked to the plasma membrane, where it interacts with 67LR, protecting it from ubiquitin-mediated degradation (23).…”

mentioning

confidence: 99%

HIV-1 Exploits a Dynamic Multi-aminoacyl-tRNA Synthetase Complex To Enhance Viral Replication

Duchon

Gelais

Titkemeier

et al. 2017

J Virol

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A hallmark of retroviruses such as human immunodeficiency virus type 1 (HIV-1) is reverse transcription of genomic RNA to DNA, a process that is primed by cellular tRNAs. HIV-1 recruits human tRNA Lys3 to serve as the reverse transcription primer via an interaction between lysyl-tRNA synthetase (LysRS) and the HIV-1 Gag polyprotein. LysRS is normally sequestered in a multi-aminoacyltRNA synthetase complex (MSC). Previous studies demonstrated that components of the MSC can be mobilized in response to certain cellular stimuli, but how LysRS is redirected from the MSC to viral particles for packaging is unknown. Here, we show that upon HIV-1 infection, a free pool of non-MSC-associated LysRS is observed and partially relocalized to the nucleus. Heat inactivation of HIV-1 blocks nuclear localization of LysRS, but treatment with a reverse transcriptase inhibitor does not, suggesting that the trigger for relocalization occurs prior to reverse transcription. A reduction in HIV-1 infection is observed upon treatment with an inhibitor to mitogen-activated protein kinase that prevents phosphorylation of LysRS on Ser207, release of LysRS from the MSC, and nuclear localization. A phosphomimetic mutant of LysRS (S207D) that lacked the capability to aminoacylate tRNA Lys3 localized to the nucleus, rescued HIV-1 infectivity, and was packaged into virions. In contrast, a phosphoablative mutant (S207A) remained cytosolic and maintained full aminoacylation activity but failed to rescue infectivity and was not packaged. These findings suggest that HIV-1 takes advantage of the dynamic nature of the MSC to redirect and coopt cellular translation factors to enhance viral replication.IMPORTANCE Human tRNA Lys3 , the primer for reverse transcription, and LysRS are essential host factors packaged into HIV-1 virions. Previous studies found that tRNA Lys3 packaging depends on interactions between LysRS and HIV-1 Gag; however, many details regarding the mechanism of tRNA Lys3 and LysRS packaging remain unknown. LysRS is normally sequestered in a high-molecular-weight multi-aminoacyl-tRNA synthetase complex (MSC), restricting the pool of free LysRS-tRNA Lys . Mounting evidence suggests that LysRS is released under a variety of stimuli to perform alternative functions within the cell. Here, we show that HIV-1 infection results in a free pool of LysRS that is relocalized to the nucleus of target cells. Blocking this pathway in HIV-1-producing cells resulted in less infectious progeny virions. Understanding the mechanism by which LysRS is recruited into the viral assembly pathway can be exploited for the development of specific and effective therapeutics targeting this nontranslational function.KEYWORDS lysyl-tRNA synthetase, human immunodeficiency virus, multisynthetase complex, nuclear localization, tRNA primer packaging

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Importin Beta Plays an Essential Role in the Regulation of the LysRS-Ap₄A Pathway in Immunologically Activated Mast Cells

Abstract: We recently reported that diadenosine tetraphosphate hydrolase (Ap

Cited by 17 publications

References 39 publications

Diadenosine polyphosphates (Ap₃A and Ap₄A) behave as alarmones triggering the synthesis of enzymes of the phenylpropanoid pathway in Arabidopsis thaliana

Diadenosine polyphosphates (Ap₃A and Ap₄A) behave as alarmones triggering the synthesis of enzymes of the phenylpropanoid pathway in Arabidopsis thaliana

Structural and functional attributes of malaria parasite diadenosine tetraphosphate hydrolase

HIV-1 Exploits a Dynamic Multi-aminoacyl-tRNA Synthetase Complex To Enhance Viral Replication

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Importin Beta Plays an Essential Role in the Regulation of the LysRS-Ap4A Pathway in Immunologically Activated Mast Cells

Abstract: We recently reported that diadenosine tetraphosphate hydrolase (Ap

Cited by 17 publications

References 39 publications

Diadenosine polyphosphates (Ap3A and Ap4A) behave as alarmones triggering the synthesis of enzymes of the phenylpropanoid pathway in Arabidopsis thaliana

Diadenosine polyphosphates (Ap3A and Ap4A) behave as alarmones triggering the synthesis of enzymes of the phenylpropanoid pathway in Arabidopsis thaliana

Structural and functional attributes of malaria parasite diadenosine tetraphosphate hydrolase

HIV-1 Exploits a Dynamic Multi-aminoacyl-tRNA Synthetase Complex To Enhance Viral Replication

Contact Info

Product

Resources

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Importin Beta Plays an Essential Role in the Regulation of the LysRS-Ap₄A Pathway in Immunologically Activated Mast Cells

Diadenosine polyphosphates (Ap₃A and Ap₄A) behave as alarmones triggering the synthesis of enzymes of the phenylpropanoid pathway in Arabidopsis thaliana

Diadenosine polyphosphates (Ap₃A and Ap₄A) behave as alarmones triggering the synthesis of enzymes of the phenylpropanoid pathway in Arabidopsis thaliana