Transient arrest in proteasomal degradation during inhibition of translation in the unfolded protein response.
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.
Shenkman
Marina
M
Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Tolchinsky
Sandra
S
Kondratyev
Maria
M
Lederkremer
Gerardo Z
GZ
D000818:Animals; D037263:Asialoglycoprotein Receptor / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D003513:Cycloheximide / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D014176:Protein Biosynthesis; D011487:Protein Conformation; D017510:Protein Folding; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D037263:Asialoglycoprotein Receptor; D011500:Protein Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003513:Cycloheximide; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex