Restoration of NF-κB activation by tumor necrosis factor alpha receptor complex-targeted MEKK3 in receptor-interacting protein-deficient cells

Marzenna Blonska, Yun You, Romas Geleziunas, Xin Lin

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Receptor-interacting protein (RIP) plays a critical role in tumor necrosis factor alpha (TNF-α)-induced NF-κB activation. However, the mechanism by which RIP mediates TNF-α-induced signal transduction is not fully understood. In this study, we reconstituted RIP-deficient Jurkat T cells with a fusion protein composed of full-length MEKK3 and the death domain of RIP (MEKK3-DD). In these cells, MEKK3-DD substitutes for RIP and directly associates with TRADD in TNF receptor complexes following TNF-α stimulation. We found that TNF-α-induced NF-κB activation was fully restored by MEKK3-DD in these cells. In contrast, expression of a fusion protein composed of NEMO, a component of the IκB kinase complex, and the death domain of RIP (NEMO-DD) cannot restore TNF-α-induced NF-κB activation in RIP-deficient cells. These results indicate that the role of RIP is to specifically recruit MEKK3 to the TNF-α receptor complex, whereas the forced recruitment of NEMO to the TNF-α receptor complex is insufficient for TNF-α-induced NF-κB activation. Although MEKK2 has a high degree of homology with MEKK3, MEKK2-DD, unlike MEKK3-DD, also fails to restore TNF-α-induced NF-κB activation in RIP-deficient cells, indicating that RIP-dependent recruitment of MEKK3 plays a specific role in TNF-α signaling.

Original languageEnglish (US)
Pages (from-to)10757-10765
Number of pages9
JournalMolecular and Cellular Biology
Volume24
Issue number24
DOIs
StatePublished - Dec 2004
Externally publishedYes

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Receptor-Interacting Protein Serine-Threonine Kinases
Tumor Necrosis Factor Receptors
Tumor Necrosis Factor-alpha
Death Domain Receptors
Jurkat Cells
Signal Transduction
Proteins
Cell Death
Phosphotransferases

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Restoration of NF-κB activation by tumor necrosis factor alpha receptor complex-targeted MEKK3 in receptor-interacting protein-deficient cells. / Blonska, Marzenna; You, Yun; Geleziunas, Romas; Lin, Xin.

In: Molecular and Cellular Biology, Vol. 24, No. 24, 12.2004, p. 10757-10765.

Research output: Contribution to journalArticle

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