Molecular symbiosis of CHOP and C/EBP beta isoform LIP contributes to endoplasmic reticulum stress-induced apoptosis.
Induction of the transcription factor CHOP (CCAAT-binding homologous protein; GADD 153) is a critical cellular response for the transcriptional control of endoplasmic reticulum (ER) stress-induced apoptosis. Upon nuclear translocation, CHOP upregulates the transcription of proapoptotic factors and downregulates antiapoptotic genes. Transcriptional activation by CHOP involves heterodimerization with other members of the basic leucine zipper transcription factor (bZIP) family. We show that the bZIP protein C/EBP beta isoform LIP is required for nuclear translocation of CHOP during ER stress. In early ER stress, LIP undergoes proteasomal degradation in the cytoplasmic compartment. During later ER stress, LIP binds CHOP in both cytoplasmic and nuclear compartments and contributes to its nuclear import. By using CHOP-deficient cells and transfections of LIP-expressing vectors in C/EBP beta(-/-) mouse embryonic fibroblasts (MEFs), we show that the LIP-CHOP interaction has a stabilizing role for LIP. At the same time, CHOP uses LIP as a vehicle for nuclear import. LIP-expressing C/EBP beta(-/-) MEFs showed enhanced ER stress-induced apoptosis compared to C/EBP beta-null cells, a finding in agreement with the decreased levels of Bcl-2, a known transcriptional control target of CHOP. In view of the positive effect of CHOP-LIP interaction in mediating their proapoptotic functions, we propose this functional cooperativity as molecular symbiosis between proteins.
Chiribau
Calin-Bogdan
CB
Department of Nutrition, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4954, USA.
Gaccioli
Francesca
F
Huang
Charlie C
CC
Yuan
Celvie L
CL
Hatzoglou
Maria
M
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D051379:Mice; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D051742:Transcription Factor CHOP / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D022782:CCAAT-Enhancer-Binding Protein-beta; D017931:DNA Primers; C497250:Ddit3 protein, mouse; D020033:Protein Isoforms; D011994:Recombinant Proteins; D051742:Transcription Factor CHOP