Phosphorylation of eukaryotic translation initiation factor 2alpha coordinates rRNA transcription and translation inhibition during endoplasmic reticulum stress.
The endoplasmic reticulum (ER) is the major cellular compartment where folding and maturation of secretory and membrane proteins take place. When protein folding needs exceed the capacity of the ER, the unfolded protein response (UPR) pathway modulates gene expression and downregulates protein translation to restore homeostasis. Here, we report that the UPR downregulates the synthesis of rRNA by inactivation of the RNA polymerase I basal transcription factor RRN3/TIF-IA. Inhibition of rRNA synthesis does not appear to involve the well-characterized mTOR (mammalian target of rapamycin) pathway; instead, PERK-dependent phosphorylation of eIF2alpha plays a critical role in the inactivation of RRN3/TIF-IA. Downregulation of rRNA transcription occurs simultaneously or slightly prior to eIF2alpha phosphorylation-induced translation repression. Since rRNA is the most abundant RNA species, constituting approximately 90% of total cellular RNA, its downregulation exerts a significant impact on cell physiology. Our study demonstrates the first link between regulation of translation and rRNA synthesis with phosphorylation of eIF2alpha, suggesting that this pathway may be broadly utilized by stresses that activate eIF2alpha kinases in order to coordinately regulate translation and ribosome biogenesis during cellular stress.
DuRose
Jenny B
JB
Division of Biological Sciences, University of California-San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
Scheuner
Donalyn
D
Kaufman
Randal J
RJ
Rothblum
Lawrence I
LI
Niwa
Maho
M
D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D035463:Pol1 Transcription Initiation Complex Proteins; D014176:Protein Biosynthesis; D017510:Protein Folding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D012335:RNA, Ribosomal / Q000235:genetics*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D015852:Eukaryotic Initiation Factor-2; D035463:Pol1 Transcription Initiation Complex Proteins; D011494:Protein Kinases; D012335:RNA, Ribosomal; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D019892:eIF-2 Kinase; C428423:RRN3 protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse