Central role of the scaffold protein tumor necrosis factor receptor-associated factor 2 in regulating endoplasmic reticulum stress-induced apoptosis.
The endoplasmic reticulum represents the quality control site of the cell for folding and assembly of cargo proteins. A variety of conditions can alter the ability of the endoplasmic reticulum (ER) to properly fold proteins, thus resulting in ER stress. Cells respond to ER stress by activating different signal transduction pathways leading to increased transcription of chaperone genes, decreased protein synthesis, and eventually to apoptosis. In the present paper we analyzed the role that the adaptor protein tumor necrosis factor-receptor associated factor 2 (TRAF2) plays in regulating cellular responses to apoptotic stimuli from the endoplasmic reticulum. Mouse embryonic fibroblasts derived from TRAF2-/- mice were more susceptible to apoptosis induced by ER stress than the wild type counterpart. This increased susceptibility to ER stress-induced apoptosis was because of an increased accumulation of reactive oxygen species following ER stress, and was abolished by the use of antioxidant. In addition, we demonstrated that the NF-kappaB pathway protects cells from ER stress-induced apoptosis, controlling ROS accumulation. Our results underscore the involvement of TRAF2 in regulating ER stress responses and the role of NF-kappaB in protecting cells from ER stress-induced apoptosis.
Mauro
Claudio
C
Dipartimento di Biologia e Patologia Cellulare e Molecolare and Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II," Via Pansini 5, 80131 Naples, Italy.
Crescenzi
Elvira
E
De Mattia
Roberta
R
Pacifico
Francesco
F
Mellone
Stefano
S
Salzano
Salvatore
S
de Luca
Cristiana
C
D'Adamio
Luciano
L
Palumbo
Giuseppe
G
Formisano
Silvestro
S
Vito
Pasquale
P
Leonardi
Antonio
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000172:deficiency / Q000502:physiology*; D019892:eIF-2 Kinase
D000975:Antioxidants; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D047992:TNF Receptor-Associated Factor 2; D019892:eIF-2 Kinase; D048031:JNK Mitogen-Activated Protein Kinases