In TNF-stimulated cells, RIPK1 promotes cell survival by stabilizing TRAF2 and cIAP1, which limits induction of non-canonical NF-kappaB and activation of caspase-8.
J Biol Chem
; 286(15): 13282-91, 2011 Apr 15.
Article
in En
| MEDLINE
| ID: mdl-21339290
ABSTRACT
RIPK1 is involved in signaling from TNF and TLR family receptors. After receptor ligation, RIPK1 not only modulates activation of both canonical and NIK-dependent NF-κB, but also regulates caspase-8 activation and cell death. Although overexpression of RIPK1 can cause caspase-8-dependent cell death, when RIPK1(-/-) cells are exposed to TNF and low doses of cycloheximide, they die more readily than wild-type cells, indicating RIPK1 has pro-survival as well as pro-apoptotic activities. To determine how RIPK1 promotes cell survival, we compared wild-type and RIPK1(-/-) cells treated with TNF. Although TRAF2 levels remained constant in TNF-treated wild-type cells, TNF stimulation of RIPK1(-/-) cells caused TRAF2 and cIAP1 to be rapidly degraded by the proteasome, which led to an increase in NIK levels. This resulted in processing of p100 NF-κB2 to p52, a decrease in levels of cFLIP(L), and activation of caspase-8, culminating in cell death. Therefore, the pro-survival effect of RIPK1 is mediated by stabilization of TRAF2 and cIAP1.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
NF-kappa B
/
Tumor Necrosis Factor-alpha
/
TNF Receptor-Associated Factor 2
/
Inhibitor of Apoptosis Proteins
/
Caspase 8
/
Receptor-Interacting Protein Serine-Threonine Kinases
Limits:
Animals
Language:
En
Journal:
J Biol Chem
Year:
2011
Type:
Article
Affiliation country:
Australia