Advanced

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

Rizk, John ; Kaplinsky, Joseph ; Agerholm, Rasmus ; Kadekar, Darshana ; Ivars, Fredrik LU ; Agace, William W. LU ; Wei-Lynn Wong, W. ; Szucs, Matthew J. ; Myers, Samuel A. and Carr, Steven A. , et al. (2019) In Science Signaling 12(596).
Abstract

Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) are selective antagonists of the inhibitor of apoptosis proteins (IAPs), which activate noncanonical NF-B signaling and promote tumor cell death. Through gene expression analysis, we found that treatment of CD4+ T cells with SMs during T helper 17 (TH17) 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-B signaling. Whereas SMs inhibited interleukin-17 (IL-17) production and ameliorated TH17 cell-driven... (More)

Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) are selective antagonists of the inhibitor of apoptosis proteins (IAPs), which activate noncanonical NF-B signaling and promote tumor cell death. Through gene expression analysis, we found that treatment of CD4+ T cells with SMs during T helper 17 (TH17) 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-B signaling. Whereas SMs inhibited interleukin-17 (IL-17) production and ameliorated TH17 cell-driven inflammation, they stimulated IL-22 secretion. Mechanistically, SM-mediated activation of NF-B-inducing kinase (NIK) and the transcription factors RelB and p52 directly suppressed Il17a 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+ T cells into TH2 cells rather than TH17 cells. These results demonstrate that SMs shape the gene expression and protein profiles of TH17 cells and inhibit TH17 cell-driven autoimmunity.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Signaling
volume
12
issue
596
article number
aaw3469
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85071640014
  • pmid:31455723
ISSN
1945-0877
DOI
10.1126/scisignal.aaw3469
language
English
LU publication?
yes
id
9ddf7583-09ff-4701-b27d-66a382e51d06
date added to LUP
2019-09-18 12:37:06
date last changed
2020-01-16 04:05:19
@article{9ddf7583-09ff-4701-b27d-66a382e51d06,
  abstract     = {<p>Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) are selective antagonists of the inhibitor of apoptosis proteins (IAPs), which activate noncanonical NF-B signaling and promote tumor cell death. Through gene expression analysis, we found that treatment of CD4<sup>+</sup> T cells with SMs during T helper 17 (T<sub>H</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-B signaling. Whereas SMs inhibited interleukin-17 (IL-17) production and ameliorated T<sub>H</sub>17 cell-driven inflammation, they stimulated IL-22 secretion. Mechanistically, SM-mediated activation of NF-B-inducing kinase (NIK) and the transcription factors RelB and p52 directly suppressed Il17a 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<sup>+</sup> T cells into T<sub>H</sub>2 cells rather than T<sub>H</sub>17 cells. These results demonstrate that SMs shape the gene expression and protein profiles of T<sub>H</sub>17 cells and inhibit T<sub>H</sub>17 cell-driven autoimmunity.</p>},
  author       = {Rizk, John and Kaplinsky, Joseph and Agerholm, Rasmus and Kadekar, Darshana and Ivars, Fredrik and Agace, William W. and Wei-Lynn Wong, W. and Szucs, Matthew J. and Myers, Samuel A. and Carr, Steven A. and Waisman, Ari and Bekiaris, Vasileios},
  issn         = {1945-0877},
  language     = {eng},
  number       = {596},
  publisher    = {American Association for the Advancement of Science (AAAS)},
  series       = {Science Signaling},
  title        = {SMAC mimetics promote NIK-dependent inhibition of CD4<sup>+</sup> T<sub>H</sub>17 cell differentiation},
  url          = {http://dx.doi.org/10.1126/scisignal.aaw3469},
  doi          = {10.1126/scisignal.aaw3469},
  volume       = {12},
  year         = {2019},
}