Impact of eIF2α phosphorylation on the translational landscape of mouse embryonic stem cells
Mehdi Amiri,
Stephen J. Kiniry,
Anthony P. Possemato,
Niaz Mahmood,
Tayebeh Basiri,
Catherine R. Dufour,
Negar Tabatabaei,
Qiyun Deng,
Michael A. Bellucci,
Keerthana Harwalkar,
Matthew P. Stokes,
Vincent Giguère,
Randal J. Kaufman,
Yojiro Yamanaka,
Pavel V. Baranov,
Soroush Tahmasebi,
Nahum Sonenberg
Affiliations
Mehdi Amiri
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada
Stephen J. Kiniry
School of Biochemistry and Cell Biology, University College Cork, T12 XF62 Cork, Ireland
Anthony P. Possemato
Cell Signaling Technology, Inc., 3 Trask Lane, Danvers, MA 01923, USA
Niaz Mahmood
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada
Tayebeh Basiri
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada
Catherine R. Dufour
Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada
Negar Tabatabaei
Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA
Qiyun Deng
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada
Michael A. Bellucci
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada
Keerthana Harwalkar
Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada
Matthew P. Stokes
Cell Signaling Technology, Inc., 3 Trask Lane, Danvers, MA 01923, USA
Vincent Giguère
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada
Randal J. Kaufman
Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
Yojiro Yamanaka
Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada
Pavel V. Baranov
School of Biochemistry and Cell Biology, University College Cork, T12 XF62 Cork, Ireland
Soroush Tahmasebi
Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL 60612, USA; Corresponding author
Nahum Sonenberg
Department of Biochemistry, McGill University, Montreal, QC H3A 1A3, Canada; Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada; Corresponding author
Summary: The integrated stress response (ISR) is critical for cell survival under stress. In response to diverse environmental cues, eIF2α becomes phosphorylated, engendering a dramatic change in mRNA translation. The activation of ISR plays a pivotal role in the early embryogenesis, but the eIF2-dependent translational landscape in pluripotent embryonic stem cells (ESCs) is largely unexplored. We employ a multi-omics approach consisting of ribosome profiling, proteomics, and metabolomics in wild-type (eIF2α+/+) and phosphorylation-deficient mutant eIF2α (eIF2αA/A) mouse ESCs (mESCs) to investigate phosphorylated (p)-eIF2α-dependent translational control of naive pluripotency. We show a transient increase in p-eIF2α in the naive epiblast layer of E4.5 embryos. Absence of eIF2α phosphorylation engenders an exit from naive pluripotency following 2i (two chemical inhibitors of MEK1/2 and GSK3α/β) withdrawal. p-eIF2α controls translation of mRNAs encoding proteins that govern pluripotency, chromatin organization, and glutathione synthesis. Thus, p-eIF2α acts as a key regulator of the naive pluripotency gene regulatory network.
