Molecular Symbiosis of CHOP and C/EBPβ Isoform LIP Contributes to Endoplasmic Reticulum Stress-Induced Apoptosis

Abstract

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/EBPβ 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/EBPβ^−/− 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/EBPβ^−/− MEFs showed enhanced ER stress-induced apoptosis compared to C/EBPβ-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.

C.-B.C. dedicates this study to Roderich Brandsch (University of Freiburg, Freiburg, Germany).

C.-B.C. thanks Cristinel Sandu (Rockefeller University) for critical reading of the manuscript. We thank Ronald Wek (Indiana University) for providing the CHOP^−/− MEFs and Peter F. Johnson (National Cancer Institute—Frederick) for the C/EBPβ^−/− MEFs. Chuanping Wang is acknowledged for excellent technical assistance, and Elena Bevilacqua is acknowledged for fruitful discussions.

This study was supported by grants R01DK060596 and R01DK053307 to M.H. from the National Institutes of Health.