IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production

Hao Zhou, Minjia Yu, Koichi Fukuda, Jinteak Im, Peng Yao, Wei Cui, Katarzyna Bulek, Jarod Zepp, Youzhong Wan, Tae Whan Kim, Weiguo Yin, Victoria Ma, James Thomas, Jun Gu, Jian An Wang, Paul E. Dicorleto, Paul L. Fox, Jun Qin, Xiaoxia Li

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Toll-like receptors transduce their signals through the adaptor molecule MyD88 and members of the IL-1R-associated kinase family (IRAK-1, 2, M and 4). IRAK-1 and IRAK-2, known to form Myddosomes with MyD88-IRAK-4, mediate TLR7-induced TAK1-dependent NFκB activation. IRAK-M was previously known to function as a negative regulator that prevents the dissociation of IRAKs from MyD88, thereby inhibiting downstream signalling. However, we now found that IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFκB activation, which is uncoupled from post-transcriptional regulation. As a result, the IRAK-M-dependent pathway only induced expression of genes that are not regulated at the post-transcriptional levels (including inhibitory molecules SOCS1, SHIP1, A20 and IκBα), exerting an overall inhibitory effect on inflammatory response. On the other hand, through interaction with IRAK-2, IRAK-M inhibited TLR7-mediated production of cytokines and chemokines at translational levels. Taken together, IRAK-M mediates TLR7-induced MEKK3-dependent second wave NFκB activation to produce inhibitory molecules as a negative feedback for the pathway, while exerting inhibitory effect on translational control of cytokines and chemokines.

Original languageEnglish (US)
Pages (from-to)583-596
Number of pages14
JournalEMBO Journal
Volume32
Issue number4
DOIs
StatePublished - Feb 20 2013

Fingerprint

Toll-Like Receptors
Chemokines
Interleukin-1 Receptor-Associated Kinases
Chemical activation
Cytokines
Molecules
Gene Expression
Phosphotransferases
Genes
Feedback

Keywords

  • IRAK
  • myddosome
  • signalling
  • Toll-like receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Cite this

Zhou, H., Yu, M., Fukuda, K., Im, J., Yao, P., Cui, W., ... Li, X. (2013). IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production. EMBO Journal, 32(4), 583-596. https://doi.org/10.1038/emboj.2013.2

IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production. / Zhou, Hao; Yu, Minjia; Fukuda, Koichi; Im, Jinteak; Yao, Peng; Cui, Wei; Bulek, Katarzyna; Zepp, Jarod; Wan, Youzhong; Whan Kim, Tae; Yin, Weiguo; Ma, Victoria; Thomas, James; Gu, Jun; Wang, Jian An; Dicorleto, Paul E.; Fox, Paul L.; Qin, Jun; Li, Xiaoxia.

In: EMBO Journal, Vol. 32, No. 4, 20.02.2013, p. 583-596.

Research output: Contribution to journalArticle

Zhou, H, Yu, M, Fukuda, K, Im, J, Yao, P, Cui, W, Bulek, K, Zepp, J, Wan, Y, Whan Kim, T, Yin, W, Ma, V, Thomas, J, Gu, J, Wang, JA, Dicorleto, PE, Fox, PL, Qin, J & Li, X 2013, 'IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production', EMBO Journal, vol. 32, no. 4, pp. 583-596. https://doi.org/10.1038/emboj.2013.2
Zhou, Hao ; Yu, Minjia ; Fukuda, Koichi ; Im, Jinteak ; Yao, Peng ; Cui, Wei ; Bulek, Katarzyna ; Zepp, Jarod ; Wan, Youzhong ; Whan Kim, Tae ; Yin, Weiguo ; Ma, Victoria ; Thomas, James ; Gu, Jun ; Wang, Jian An ; Dicorleto, Paul E. ; Fox, Paul L. ; Qin, Jun ; Li, Xiaoxia. / IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production. In: EMBO Journal. 2013 ; Vol. 32, No. 4. pp. 583-596.
@article{baced6e9900e4c6f87d936f8ce042f92,
title = "IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production",
abstract = "Toll-like receptors transduce their signals through the adaptor molecule MyD88 and members of the IL-1R-associated kinase family (IRAK-1, 2, M and 4). IRAK-1 and IRAK-2, known to form Myddosomes with MyD88-IRAK-4, mediate TLR7-induced TAK1-dependent NFκB activation. IRAK-M was previously known to function as a negative regulator that prevents the dissociation of IRAKs from MyD88, thereby inhibiting downstream signalling. However, we now found that IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFκB activation, which is uncoupled from post-transcriptional regulation. As a result, the IRAK-M-dependent pathway only induced expression of genes that are not regulated at the post-transcriptional levels (including inhibitory molecules SOCS1, SHIP1, A20 and IκBα), exerting an overall inhibitory effect on inflammatory response. On the other hand, through interaction with IRAK-2, IRAK-M inhibited TLR7-mediated production of cytokines and chemokines at translational levels. Taken together, IRAK-M mediates TLR7-induced MEKK3-dependent second wave NFκB activation to produce inhibitory molecules as a negative feedback for the pathway, while exerting inhibitory effect on translational control of cytokines and chemokines.",
keywords = "IRAK, myddosome, signalling, Toll-like receptor",
author = "Hao Zhou and Minjia Yu and Koichi Fukuda and Jinteak Im and Peng Yao and Wei Cui and Katarzyna Bulek and Jarod Zepp and Youzhong Wan and {Whan Kim}, Tae and Weiguo Yin and Victoria Ma and James Thomas and Jun Gu and Wang, {Jian An} and Dicorleto, {Paul E.} and Fox, {Paul L.} and Jun Qin and Xiaoxia Li",
year = "2013",
month = "2",
day = "20",
doi = "10.1038/emboj.2013.2",
language = "English (US)",
volume = "32",
pages = "583--596",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production

AU - Zhou, Hao

AU - Yu, Minjia

AU - Fukuda, Koichi

AU - Im, Jinteak

AU - Yao, Peng

AU - Cui, Wei

AU - Bulek, Katarzyna

AU - Zepp, Jarod

AU - Wan, Youzhong

AU - Whan Kim, Tae

AU - Yin, Weiguo

AU - Ma, Victoria

AU - Thomas, James

AU - Gu, Jun

AU - Wang, Jian An

AU - Dicorleto, Paul E.

AU - Fox, Paul L.

AU - Qin, Jun

AU - Li, Xiaoxia

PY - 2013/2/20

Y1 - 2013/2/20

N2 - Toll-like receptors transduce their signals through the adaptor molecule MyD88 and members of the IL-1R-associated kinase family (IRAK-1, 2, M and 4). IRAK-1 and IRAK-2, known to form Myddosomes with MyD88-IRAK-4, mediate TLR7-induced TAK1-dependent NFκB activation. IRAK-M was previously known to function as a negative regulator that prevents the dissociation of IRAKs from MyD88, thereby inhibiting downstream signalling. However, we now found that IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFκB activation, which is uncoupled from post-transcriptional regulation. As a result, the IRAK-M-dependent pathway only induced expression of genes that are not regulated at the post-transcriptional levels (including inhibitory molecules SOCS1, SHIP1, A20 and IκBα), exerting an overall inhibitory effect on inflammatory response. On the other hand, through interaction with IRAK-2, IRAK-M inhibited TLR7-mediated production of cytokines and chemokines at translational levels. Taken together, IRAK-M mediates TLR7-induced MEKK3-dependent second wave NFκB activation to produce inhibitory molecules as a negative feedback for the pathway, while exerting inhibitory effect on translational control of cytokines and chemokines.

AB - Toll-like receptors transduce their signals through the adaptor molecule MyD88 and members of the IL-1R-associated kinase family (IRAK-1, 2, M and 4). IRAK-1 and IRAK-2, known to form Myddosomes with MyD88-IRAK-4, mediate TLR7-induced TAK1-dependent NFκB activation. IRAK-M was previously known to function as a negative regulator that prevents the dissociation of IRAKs from MyD88, thereby inhibiting downstream signalling. However, we now found that IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFκB activation, which is uncoupled from post-transcriptional regulation. As a result, the IRAK-M-dependent pathway only induced expression of genes that are not regulated at the post-transcriptional levels (including inhibitory molecules SOCS1, SHIP1, A20 and IκBα), exerting an overall inhibitory effect on inflammatory response. On the other hand, through interaction with IRAK-2, IRAK-M inhibited TLR7-mediated production of cytokines and chemokines at translational levels. Taken together, IRAK-M mediates TLR7-induced MEKK3-dependent second wave NFκB activation to produce inhibitory molecules as a negative feedback for the pathway, while exerting inhibitory effect on translational control of cytokines and chemokines.

KW - IRAK

KW - myddosome

KW - signalling

KW - Toll-like receptor

UR - http://www.scopus.com/inward/record.url?scp=84875219876&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875219876&partnerID=8YFLogxK

U2 - 10.1038/emboj.2013.2

DO - 10.1038/emboj.2013.2

M3 - Article

VL - 32

SP - 583

EP - 596

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

IS - 4

ER -