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 language | English (US) |
|---|---|
| Pages (from-to) | 10757-10765 |
| Number of pages | 9 |
| Journal | Molecular and Cellular Biology |
| Volume | 24 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 2004 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cell Biology
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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 journal › Article
}
TY - JOUR
T1 - Restoration of NF-κB activation by tumor necrosis factor alpha receptor complex-targeted MEKK3 in receptor-interacting protein-deficient cells
AU - Blonska, Marzenna
AU - You, Yun
AU - Geleziunas, Romas
AU - Lin, Xin
PY - 2004/12
Y1 - 2004/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=10044298518&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=10044298518&partnerID=8YFLogxK
U2 - 10.1128/MCB.24.24.10757-10765.2004
DO - 10.1128/MCB.24.24.10757-10765.2004
M3 - Article
C2 - 15572679
AN - SCOPUS:10044298518
VL - 24
SP - 10757
EP - 10765
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
SN - 0270-7306
IS - 24
ER -