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SMAC mimetics promote NIK-dependent inhibition of CD4+ TH17 cell differentiation


Rizk, John; Kaplinsky, Joseph; Agerholm, Rasmus; Kadekar, Darshana; Ivars, Fredrik; Agace, William W; Wong, W Wei-Lynn; Szucs, Matthew J; Myers, Samuel A; Carr, Steven A; Waisman, Ari; Bekiaris, Vasileios (2019). SMAC mimetics promote NIK-dependent inhibition of CD4+ TH17 cell differentiation. Science Signaling, 12(596):eaaw3469.

Abstract

Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) are selective antagonists of the inhibitor of apoptosis proteins (IAPs), which activate noncanonical NF-κB signaling and promote tumor cell death. Through gene expression analysis, we found that treatment of CD4<jats:sup>+</jats:sup> T cells with SMs during T helper 17 (T<jats:sub>H</jats:sub>17) cell differentiation disrupted the balance between two antagonistic transcription factor modules. Moreover, proteomics analysis revealed that SMs altered the abundance of proteins associated with cell cycle, mitochondrial activity, and the balance between canonical and noncanonical NF-κB signaling. Whereas SMs inhibited interleukin-17 (IL-17) production and ameliorated T<jats:sub>H</jats:sub>17 cell–driven inflammation, they stimulated IL-22 secretion. Mechanistically, SM-mediated activation of NF-κB–inducing kinase (NIK) and the transcription factors RelB and p52 directly suppressed <jats:italic>Il17a</jats:italic> expression and IL-17A protein production, as well as the expression of a number of other immune genes. Induction of IL-22 production correlated with the NIK-dependent reduction in cMAF protein abundance and the enhanced activity of the aryl hydrocarbon receptor. Last, SMs also increased IL-9 and IL-13 production and, under competing conditions, favored the differentiation of naïve CD4<jats:sup>+</jats:sup> T cells into T<jats:sub>H</jats:sub>2 cells rather than T<jats:sub>H</jats:sub>17 cells. These results demonstrate that SMs shape the gene expression and protein profiles of T<jats:sub>H</jats:sub>17 cells and inhibit T<jats:sub>H</jats:sub>17 cell–driven autoimmunity.

Abstract

Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) are selective antagonists of the inhibitor of apoptosis proteins (IAPs), which activate noncanonical NF-κB signaling and promote tumor cell death. Through gene expression analysis, we found that treatment of CD4<jats:sup>+</jats:sup> T cells with SMs during T helper 17 (T<jats:sub>H</jats:sub>17) cell differentiation disrupted the balance between two antagonistic transcription factor modules. Moreover, proteomics analysis revealed that SMs altered the abundance of proteins associated with cell cycle, mitochondrial activity, and the balance between canonical and noncanonical NF-κB signaling. Whereas SMs inhibited interleukin-17 (IL-17) production and ameliorated T<jats:sub>H</jats:sub>17 cell–driven inflammation, they stimulated IL-22 secretion. Mechanistically, SM-mediated activation of NF-κB–inducing kinase (NIK) and the transcription factors RelB and p52 directly suppressed <jats:italic>Il17a</jats:italic> expression and IL-17A protein production, as well as the expression of a number of other immune genes. Induction of IL-22 production correlated with the NIK-dependent reduction in cMAF protein abundance and the enhanced activity of the aryl hydrocarbon receptor. Last, SMs also increased IL-9 and IL-13 production and, under competing conditions, favored the differentiation of naïve CD4<jats:sup>+</jats:sup> T cells into T<jats:sub>H</jats:sub>2 cells rather than T<jats:sub>H</jats:sub>17 cells. These results demonstrate that SMs shape the gene expression and protein profiles of T<jats:sub>H</jats:sub>17 cells and inhibit T<jats:sub>H</jats:sub>17 cell–driven autoimmunity.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Molecular Biology
Life Sciences > Cell Biology
Uncontrolled Keywords:Cell Biology, Biochemistry, Molecular Biology
Language:English
Date:27 August 2019
Deposited On:09 Mar 2020 10:06
Last Modified:29 Jul 2020 14:51
Publisher:American Association for the Advancement of Science
ISSN:1945-0877
OA Status:Green
Publisher DOI:https://doi.org/10.1126/scisignal.aaw3469
PubMed ID:31455723

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