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Article ; Online: Oligoadenylate synthetase 1 displays dual antiviral mechanisms in driving translational shutdown and protecting interferon production.

Harioudh, Munesh K / Perez, Joseph / Chong, Zhenlu / Nair, Sharmila / So, Lomon / McCormick, Kevin D / Ghosh, Arundhati / Shao, Lulu / Srivastava, Rashmi / Soveg, Frank / Ebert, Thomas S / Atianand, Maninjay K / Hornung, Veit / Savan, Ram / Diamond, Michael S / Sarkar, Saumendra N

Immunity

2024 Volume 57, Issue 3, Page(s) 446–461.e7

Abstract: In response to viral infection, how cells balance translational shutdown to limit viral replication and the induction of antiviral components like interferons (IFNs) is not well understood. Moreover, how distinct isoforms of IFN-induced oligoadenylate ... ...

Abstract	In response to viral infection, how cells balance translational shutdown to limit viral replication and the induction of antiviral components like interferons (IFNs) is not well understood. Moreover, how distinct isoforms of IFN-induced oligoadenylate synthetase 1 (OAS1) contribute to this antiviral response also requires further elucidation. Here, we show that human, but not mouse, OAS1 inhibits SARS-CoV-2 replication through its canonical enzyme activity via RNase L. In contrast, both mouse and human OAS1 protect against West Nile virus infection by a mechanism distinct from canonical RNase L activation. OAS1 binds AU-rich elements (AREs) of specific mRNAs, including IFNβ. This binding leads to the sequestration of IFNβ mRNA to the endomembrane regions, resulting in prolonged half-life and continued translation. Thus, OAS1 is an ARE-binding protein with two mechanisms of antiviral activity: driving inhibition of translation but also a broader, non-canonical function of protecting IFN expression from translational shutdown.
MeSH term(s)	Animals ; Humans ; Mice ; Interferons ; Virus Diseases ; Adenine Nucleotides ; Antiviral Agents/pharmacology ; 2',5'-Oligoadenylate Synthetase/genetics ; 2',5'-Oligoadenylate Synthetase/metabolism ; Oligoribonucleotides
Chemical Substances	2',5'-oligoadenylate (61172-40-5) ; Interferons (9008-11-1) ; Adenine Nucleotides ; Antiviral Agents ; 2',5'-Oligoadenylate Synthetase (EC 2.7.7.84) ; Oligoribonucleotides
Language	English
Publishing date	2024-02-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2024.02.002
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Zs.A 4227: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Regulatory T cells suppress CD4+ effector T cell activation by controlling protein synthesis.

So, Lomon / Obata-Ninomiya, Kazushige / Hu, Alex / Muir, Virginia S / Takamori, Ayako / Song, Jing / Buckner, Jane H / Savan, Ram / Ziegler, Steven F

The Journal of experimental medicine

2023 Volume 220, Issue 3

Abstract: Regulatory T cells (Tregs) suppress the activation and subsequent effector functions of CD4 effector T cells (Teffs). However, molecular mechanisms that enforce Treg-mediated suppression in CD4 Teff are unclear. We found that Tregs suppressed activation- ... ...

Abstract	Regulatory T cells (Tregs) suppress the activation and subsequent effector functions of CD4 effector T cells (Teffs). However, molecular mechanisms that enforce Treg-mediated suppression in CD4 Teff are unclear. We found that Tregs suppressed activation-induced global protein synthesis in CD4 Teffs prior to cell division. We analyzed genome-wide changes in the transcriptome and translatome of activated CD4 Teffs. We show that mRNAs encoding for the protein synthesis machinery are regulated at the level of translation in activated CD4 Teffs by Tregs. Tregs suppressed global protein synthesis of CD4 Teffs by specifically inhibiting mRNAs of the translation machinery at the level of mTORC1-mediated translation control through concerted action of immunosuppressive cytokines IL-10 and TGFβ. Lastly, we found that the therapeutic targeting of protein synthesis with the RNA helicase eIF4A inhibitor rocaglamide A can alleviate inflammatory CD4 Teff activation caused by acute Treg depletion in vivo. These data show that peripheral tolerance is enforced by Tregs through mRNA translational control in CD4 Teffs.
MeSH term(s)	T-Lymphocytes, Regulatory ; CD4-Positive T-Lymphocytes ; Lymphocyte Activation ; Cytokines/metabolism ; Transforming Growth Factor beta/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
Chemical Substances	Cytokines ; Transforming Growth Factor beta ; RNA, Messenger
Language	English
Publishing date	2023-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20221676
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Article ; Online: Re-evaluating Strategies to Define the Immunoregulatory Roles of miRNAs.

Forero, Adriana / So, Lomon / Savan, Ram

Trends in immunology

2017 Volume 38, Issue 8, Page(s) 558–566

Abstract: miRNAs play an important role in fine-tuning host immune homeostasis and responses through the regulation of mRNA stability and translation. Studies have demonstrated that miRNA-mediated regulation of gene expression has a profound impact on immune cell ... ...

Abstract	miRNAs play an important role in fine-tuning host immune homeostasis and responses through the regulation of mRNA stability and translation. Studies have demonstrated that miRNA-mediated regulation of gene expression has a profound impact on immune cell development, function, and response to invading pathogens. As we continue to examine the mechanisms by which miRNAs maintain the balance between robust protective host immune responses and dysregulated responses that promote immune pathology, careful consideration of the complexity of post-transcriptional immune regulation is needed. Distinct tissue- and stimulus-specific RNA-RNA and RNA-protein interactions can modulate the functions of a given miRNA. Thus, new challenges emerge in the identification of post-transcriptional coregulatory modules and the genetic factors that impact miRNA function.
MeSH term(s)	3' Untranslated Regions/immunology ; Animals ; Genetic Variation/immunology ; Humans ; MicroRNAs/genetics ; MicroRNAs/immunology ; MicroRNAs/metabolism ; RNA Processing, Post-Transcriptional/immunology ; RNA Stability/immunology ; RNA, Long Noncoding/immunology ; RNA, Messenger/chemistry ; RNA, Messenger/immunology ; RNA-Binding Proteins/immunology ; RNA-Binding Proteins/metabolism
Chemical Substances	3' Untranslated Regions ; MicroRNAs ; RNA, Long Noncoding ; RNA, Messenger ; RNA-Binding Proteins
Language	English
Publishing date	2017-06-27
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2036831-8
ISSN	1471-4981 ; 1471-4906
ISSN (online)	1471-4981
ISSN	1471-4906
DOI	10.1016/j.it.2017.06.001
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Zs.A 1601: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances.

So, Lomon / Fruman, David A

The Biochemical journal

2012 Volume 442, Issue 3, Page(s) 465–481

Abstract: Activation of PI3K (phosphoinositide 3-kinase) is a shared response to engagement of diverse types of transmembrane receptors. Depending on the cell type and stimulus, PI3K activation can promote different fates including proliferation, survival, ... ...

Abstract	Activation of PI3K (phosphoinositide 3-kinase) is a shared response to engagement of diverse types of transmembrane receptors. Depending on the cell type and stimulus, PI3K activation can promote different fates including proliferation, survival, migration and differentiation. The diverse roles of PI3K signalling are well illustrated by studies of lymphocytes, the cells that mediate adaptive immunity. Genetic and pharmacological experiments have shown that PI3K activation regulates many steps in the development, activation and differentiation of both B- and T-cells. These findings have prompted the development of PI3K inhibitors for the treatment of autoimmunity and inflammatory diseases. PI3K activation, however, has both positive and negative roles in immune system activation. Consequently, although PI3K suppression can attenuate immune responses it can also enhance inflammation, disrupt peripheral tolerance and promote autoimmunity. An exciting discovery is that a selective inhibitor of the p110δ catalytic isoform of PI3K, CAL-101, achieves impressive clinical efficacy in certain B-cell malignancies. A model is emerging in which p110δ inhibition disrupts signals from the lymphoid microenvironment, leading to release of leukaemia and lymphoma cells from their protective niche. These encouraging findings have given further momentum to PI3K drug development efforts in both cancer and immune diseases.
MeSH term(s)	Animals ; B-Lymphocytes/metabolism ; Cell Communication ; Humans ; Models, Biological ; Phosphatidylinositol 3-Kinases/metabolism ; Signal Transduction ; T-Lymphocytes/metabolism
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-)
Language	English
Publishing date	2012-02-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BJ20112092
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Article ; Online: Germline SAMD9L truncation variants trigger global translational repression.

Allenspach, Eric J / Soveg, Frank / Finn, Laura S / So, Lomon / Gorman, Jacquelyn A / Rosen, Aaron B I / Skoda-Smith, Suzanne / Wheeler, Marsha M / Barrow, Kaitlyn A / Rich, Lucille M / Debley, Jason S / Bamshad, Michael J / Nickerson, Deborah A / Savan, Ram / Torgerson, Troy R / Rawlings, David J

The Journal of experimental medicine

2021 Volume 218, Issue 5

Abstract: SAMD9L is an interferon-induced tumor suppressor implicated in a spectrum of multisystem disorders, including risk for myeloid malignancies and immune deficiency. We identified a heterozygous de novo frameshift variant in SAMD9L in an infant with B cell ... ...

Abstract	SAMD9L is an interferon-induced tumor suppressor implicated in a spectrum of multisystem disorders, including risk for myeloid malignancies and immune deficiency. We identified a heterozygous de novo frameshift variant in SAMD9L in an infant with B cell aplasia and clinical autoinflammatory features who died from respiratory failure with chronic rhinovirus infection. Autopsy demonstrated absent bone marrow and peripheral B cells as well as selective loss of Langerhans and Purkinje cells. The frameshift variant led to expression of a truncated protein with interferon treatment. This protein exhibited a gain-of-function phenotype, resulting in interference in global protein synthesis via inhibition of translational elongation. Using a mutational scan, we identified a region within SAMD9L where stop-gain variants trigger a similar translational arrest. SAMD9L variants that globally suppress translation had no effect or increased mRNA transcription. The complex-reported phenotype likely reflects lineage-dominant sensitivities to this translation block. Taken together, our findings indicate that interferon-triggered SAMD9L gain-of-function variants globally suppress translation.
MeSH term(s)	A549 Cells ; B-Lymphocytes/metabolism ; B-Lymphocytes/pathology ; Fatal Outcome ; Female ; Frameshift Mutation ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/genetics ; Germ-Line Mutation ; HEK293 Cells ; Heterozygote ; Humans ; Infant, Newborn ; Interferons/pharmacology ; Myelodysplastic Syndromes/genetics ; Myelodysplastic Syndromes/metabolism ; Protein Biosynthesis/genetics ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; Whole Genome Sequencing
Chemical Substances	SAMD9L protein, human ; Tumor Suppressor Proteins ; Interferons (9008-11-1)
Language	English
Publishing date	2021-03-16
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20201195
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Article ; Online: Reciprocal effects of rab7 deletion in activated and neglected T cells.

Roy, Saurabh Ghosh / Stevens, Michael W / So, Lomon / Edinger, Aimee L

Autophagy

2013 Volume 9, Issue 7, Page(s) 1009–1023

Abstract: Mouse models lacking proteins essential for autophagosome formation have demonstrated that autophagy plays a critical role in T cell development and activation. To better understand the function of autophagy in quiescent and activated lymphocytes, we ... ...

Abstract	Mouse models lacking proteins essential for autophagosome formation have demonstrated that autophagy plays a critical role in T cell development and activation. To better understand the function of autophagy in quiescent and activated lymphocytes, we have generated a mouse deficient in rab7 selectively in T cells and compared the effects of blocking autophagy at an early (atg5(-/-)) or late (rab7(-/-)) stage on T cell biology. rab7(-/-) murine embryonic fibroblasts (MEFs) and T cells generated from these mice exhibit a profound block in autophagosome degradation and are as sensitive as atg5(-/-) cells to extracellular nutrient limitation. Rab7(flox/flox)CD4-Cre(+) mice lacking the RAB7 protein in both CD4 and CD8 T cells had reduced numbers of peripheral T cells, but this defect was not as severe as in Atg5(flox/flox)CD4-Cre(+) mice despite efficient rab7 deletion and inhibition of autophagic flux. This difference may stem from the reduced ROS generation and enhanced survival of rab7(-/-) T cells compared with wild-type and atg5(-/-) T cells in the absence of cytokine stimulation. rab7(-/-) and atg5(-/-) T cells exhibited similar defects in proliferation both following antibody-mediated T cell receptor (TCR) cross-linking and using a more physiologic activation protocol, allogeneic stimulation. Interestingly, autophagy was not required to provide building blocks for the upregulation of nutrient transporter proteins immediately following activation. Together, these studies suggest that autophagosome degradation is required for the survival of activated T cells, but that loss of rab7 is better tolerated in naïve T cells than the loss of atg5.
MeSH term(s)	Alleles ; Animals ; Autophagy ; Autophagy-Related Protein 5 ; Biomarkers/metabolism ; Embryo, Mammalian/cytology ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Gene Deletion ; Lymphocyte Activation/immunology ; Mice ; Mice, Knockout ; Microtubule-Associated Proteins/deficiency ; Microtubule-Associated Proteins/metabolism ; Mitochondria/metabolism ; Phagosomes/metabolism ; Phenotype ; Reactive Oxygen Species/metabolism ; T-Lymphocytes/metabolism ; rab GTP-Binding Proteins/deficiency ; rab GTP-Binding Proteins/metabolism
Chemical Substances	Atg5 protein, mouse ; Autophagy-Related Protein 5 ; Biomarkers ; Microtubule-Associated Proteins ; Reactive Oxygen Species ; rab7 protein (152989-05-4) ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2013-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.4161/auto.24468
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Zs.A 6741: Show issues

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Article ; Online: Resistance to mTOR kinase inhibitors in lymphoma cells lacking 4EBP1.

Mallya, Sharmila / Fitch, Briana A / Lee, J Scott / So, Lomon / Janes, Matthew R / Fruman, David A

PloS one

2014 Volume 9, Issue 2, Page(s) e88865

Abstract: Inhibitors of the mechanistic target of rapamycin (mTOR) hold promise for treatment of hematological malignancies. Analogs of the allosteric mTOR inhibitor rapamycin are approved for mantle cell lymphoma but have limited efficacy in other blood cancers. ... ...

Abstract	Inhibitors of the mechanistic target of rapamycin (mTOR) hold promise for treatment of hematological malignancies. Analogs of the allosteric mTOR inhibitor rapamycin are approved for mantle cell lymphoma but have limited efficacy in other blood cancers. ATP-competitive "active-site" mTOR inhibitors produce more complete mTOR inhibition and are more effective than rapamycin in preclinical models of leukemia, lymphoma and multiple myeloma. In parallel to clinical trials of active-site mTOR inhibitors, it will be important to identify resistance mechanisms that might limit drug efficacy in certain patients. From a panel of diffuse large B-cell lymphoma cell lines, we found that the VAL cell line is particularly resistant to apoptosis in the presence of active-site mTOR inhibitors. Mechanistic investigation showed that VAL does not express eukaryotic initiation factor 4E-binding protein-1 (4EBP1), a key negative regulator of translation controlled by mTOR. Although VAL cells express the related protein 4EBP2, mTOR inhibitor treatment fails to displace eukaryotic initiation factor 4G from the mRNA cap-binding complex. Knockdown of eukaryotic initiation factor 4E, or re-expression of 4EBP1, sensitizes cells to apoptosis when treated with active-site mTOR inhibitors. These findings provide a naturally occurring example of 4EBP deficiency driving lymphoma cell resistance to active-site mTOR inhibitors.
MeSH term(s)	Adaptor Proteins, Signal Transducing/deficiency ; Apoptosis/drug effects ; Benzoxazoles/pharmacology ; Blotting, Western ; Cell Cycle Proteins ; Cell Line, Tumor ; Drug Resistance/physiology ; Gene Knockdown Techniques ; Humans ; Lymphoma/metabolism ; Phosphoproteins/deficiency ; Pyrimidines/pharmacology ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; Tetrazolium Salts ; Thiazoles
Chemical Substances	Adaptor Proteins, Signal Transducing ; Benzoxazoles ; Cell Cycle Proteins ; EIF4EBP1 protein, human ; Phosphoproteins ; Pyrimidines ; Tetrazolium Salts ; Thiazoles ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; thiazolyl blue (EUY85H477I) ; sapanisertib (JGH0DF1U03)
Language	English
Publishing date	2014-02-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0088865
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Article ; Online: RNA-binding protein isoforms ZAP-S and ZAP-L have distinct antiviral and immune resolution functions.

Schwerk, Johannes / Soveg, Frank W / Ryan, Andrew P / Thomas, Kerri R / Hatfield, Lauren D / Ozarkar, Snehal / Forero, Adriana / Kell, Alison M / Roby, Justin A / So, Lomon / Hyde, Jennifer L / Gale, Michael / Daugherty, Matthew D / Savan, Ram

Nature immunology

2019 Volume 20, Issue 12, Page(s) 1610–1620

Abstract: The initial response to viral infection is anticipatory, with host antiviral restriction factors and pathogen sensors constantly surveying the cell to rapidly mount an antiviral response through the synthesis and downstream activity of interferons. After ...

Abstract	The initial response to viral infection is anticipatory, with host antiviral restriction factors and pathogen sensors constantly surveying the cell to rapidly mount an antiviral response through the synthesis and downstream activity of interferons. After pathogen clearance, the host's ability to resolve this antiviral response and return to homeostasis is critical. Here, we found that isoforms of the RNA-binding protein ZAP functioned as both a direct antiviral restriction factor and an interferon-resolution factor. The short isoform of ZAP bound to and mediated the degradation of several host interferon messenger RNAs, and thus acted as a negative feedback regulator of the interferon response. In contrast, the long isoform of ZAP had antiviral functions and did not regulate interferon. The two isoforms contained identical RNA-targeting domains, but differences in their intracellular localization modulated specificity for host versus viral RNA, which resulted in disparate effects on viral replication during the innate immune response.
MeSH term(s)	Alphavirus Infections/genetics ; Alphavirus Infections/immunology ; Feedback, Physiological ; HEK293 Cells ; Hep G2 Cells ; Homeostasis ; Humans ; Immunity, Innate ; Interferon Regulatory Factor-3/genetics ; Interferon Regulatory Factor-3/metabolism ; Interferons/genetics ; Protein Binding ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; RNA/genetics ; RNA/metabolism ; RNA, Small Interfering/genetics ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Sindbis Virus/physiology ; Virus Replication
Chemical Substances	IRF3 protein, human ; Interferon Regulatory Factor-3 ; Protein Isoforms ; RNA, Small Interfering ; RNA-Binding Proteins ; Repressor Proteins ; YLPM1 protein, human ; RNA (63231-63-0) ; Interferons (9008-11-1)
Language	English
Publishing date	2019-11-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-019-0527-6
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Differential Activation of the Transcription Factor IRF1 Underlies the Distinct Immune Responses Elicited by Type I and Type III Interferons.

Forero, Adriana / Ozarkar, Snehal / Li, Hongchuan / Lee, Chia Heng / Hemann, Emily A / Nadjsombati, Marija S / Hendricks, Matthew R / So, Lomon / Green, Richard / Roy, Chandra N / Sarkar, Saumendra N / von Moltke, Jakob / Anderson, Stephen K / Gale, Michael / Savan, Ram

Immunity

2019 Volume 51, Issue 3, Page(s) 451–464.e6

Abstract: Type I and III interferons (IFNs) activate similar downstream signaling cascades, but unlike type I IFNs, type III IFNs (IFNλ) do not elicit strong inflammatory responses in vivo. Here, we examined the molecular mechanisms underlying this disparity. Type ...

Abstract	Type I and III interferons (IFNs) activate similar downstream signaling cascades, but unlike type I IFNs, type III IFNs (IFNλ) do not elicit strong inflammatory responses in vivo. Here, we examined the molecular mechanisms underlying this disparity. Type I and III IFNs displayed kinetic differences in expression of IFN-stimulated genes and proinflammatory responses, with type I IFNs preferentially stimulating expression of the transcription factor IRF1. Type III IFNs failed to induce IRF1 expression because of low IFNλ receptor abundance and insufficient STAT1 activation on epithelial cells and thus did not activate the IRF1 proinflammatory gene program. Rather, IFNλ stimulation preferentially induced factors implicated in tissue repair. Our findings suggest that IFN receptor compartmentalization and abundance confer a spatiotemporal division of labor where type III IFNs control viral spread at the site of the infection while restricting tissue damage; the transient induction of inflammatory responses by type I IFNs recruits immune effectors to promote protective immunity.
MeSH term(s)	Animals ; Cell Line ; Epithelial Cells/immunology ; Humans ; Inflammation/immunology ; Interferon Regulatory Factor-1/immunology ; Interferon Type I/immunology ; Interferons/immunology ; Male ; Mice ; Mice, Inbred C57BL ; STAT1 Transcription Factor/immunology
Chemical Substances	IRF1 protein, human ; Interferon Regulatory Factor-1 ; Interferon Type I ; STAT1 Transcription Factor ; interferon type III ; Interferons (9008-11-1)
Language	English
Publishing date	2019-08-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2019.07.007
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Zs.A 4227: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Effects of novel isoform-selective phosphoinositide 3-kinase inhibitors on natural killer cell function.

Yea, Sung Su / So, Lomon / Mallya, Sharmila / Lee, Jongdae / Rajasekaran, Kamalakannan / Malarkannan, Subramaniam / Fruman, David A

PloS one

2014 Volume 9, Issue 6, Page(s) e99486

Abstract: Phosphoinositide 3-kinases (PI3Ks) are promising targets for therapeutic development in cancer. The class I PI3K isoform p110α has received considerable attention in oncology because the gene encoding p110α (PIK3CA) is frequently mutated in human cancer. ...

Abstract	Phosphoinositide 3-kinases (PI3Ks) are promising targets for therapeutic development in cancer. The class I PI3K isoform p110α has received considerable attention in oncology because the gene encoding p110α (PIK3CA) is frequently mutated in human cancer. However, little is known about the function of p110α in lymphocyte populations that modulate tumorigenesis. We used recently developed investigational inhibitors to compare the function of p110α and other isoforms in natural killer (NK) cells, a key cell type for immunosurveillance and tumor immunotherapy. Inhibitors of all class I isoforms (pan-PI3K) significantly impaired NK cell-mediated cytotoxicity and antibody-dependent cellular cytotoxicity against tumor cells, whereas p110α-selective inhibitors had no effect. In NK cells stimulated through NKG2D, p110α inhibition modestly reduced PI3K signaling output as measured by AKT phosphorylation. Production of IFN-γ and NK cell-derived chemokines was blocked by a pan-PI3K inhibitor and partially reduced by a p110δinhibitor, with lesser effects of p110α inhibitors. Oral administration of mice with MLN1117, a p110α inhibitor in oncology clinical trials, had negligible effects on NK subset maturation or terminal subset commitment. Collectively, these results support the targeting of PIK3CA mutant tumors with selective p110α inhibitors to preserve NK cell function.
MeSH term(s)	Animals ; Antibody-Dependent Cell Cytotoxicity/drug effects ; Cell Differentiation/drug effects ; Cell Survival/drug effects ; Chemokines/biosynthesis ; Cytotoxicity, Immunologic/drug effects ; Female ; Humans ; Interferon-gamma/biosynthesis ; Isoenzymes/antagonists & inhibitors ; Isoenzymes/metabolism ; Killer Cells, Natural/cytology ; Killer Cells, Natural/drug effects ; Killer Cells, Natural/enzymology ; Mice, Inbred C57BL ; NK Cell Lectin-Like Receptor Subfamily K/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-akt/metabolism
Chemical Substances	Chemokines ; Isoenzymes ; KLRK1 protein, human ; NK Cell Lectin-Like Receptor Subfamily K ; Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase Inhibitors ; Interferon-gamma (82115-62-6) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
Language	English
Publishing date	2014-06-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0099486
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Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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Order via subito

Inter-library loan at ZB MED