Transient arrest in proteasomal degradation during inhibition of translation in the unfolded protein response

• Published in: Biochemical journal Vol. 404; no. 3; pp. 509 - 516
• Main Authors: Shenkman, Marina, Tolchinsky, Sandra, Kondratyev, Maria, Lederkremer, Gerardo Z
• Format: Journal Article
• Language: English
• Published: England Portland Press Ltd 15.06.2007
• Subjects: Animals; Asialoglycoprotein Receptor - genetics; Asialoglycoprotein Receptor - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Cycloheximide - metabolism; Endoplasmic Reticulum - metabolism; Humans; Mice; NIH 3T3 Cells; Proteasome Endopeptidase Complex - metabolism; Protein Biosynthesis; Protein Conformation; Protein Folding; Protein Synthesis Inhibitors - metabolism; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Tumor Suppressor Protein p53 - metabolism; Ubiquitin - metabolism
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/bj20061854

The UPR (unfolded protein response) activates transcription of genes involved in proteasomal degradation. However, we found that in its early stages the UPR leads to a transient inhibition of proteasomal disposal of cytosolic substrates (p53 and p27kip1) and of those targeted to ER (endoplasmic reticulum)-associated degradation (uncleaved precursor of asialoglycoprotein receptor H2a). Degradation resumed soon after the protein synthesis arrest that occurs in early UPR subsided. Consistent with this, protein synthesis inhibitors blocked ubiquitin/proteasomal degradation. Ubiquitination was inhibited during the translation block, suggesting short-lived E3 ubiquitin ligases as candidate depleted proteins. This was indeed the case for p53 whose E3 ligase, Mdm2 (murine double minute 2), when overexpressed, restored the degradation, whereas a mutant Mdm2 in its acidic domain restored the ubiquitination but did not completely restore the degradation. Inhibition of proteasomal degradation early in UPR may prevent depletion of essential short-lived factors during the translation arrest. Stabilization of p27 through this mechanism may explain the cell cycle arrest in G1 when translation is blocked by inhibitors or by the UPR.