A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress.
Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, we identified salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha). Salubrinal also blocks eIF2alpha dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2alpha dephosphorylation may be useful in diseases involving ER stress or viral infection. More broadly, salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events.
Boyce
Michael
M
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Bryant
Kevin F
KF
Jousse
Céline
C
Long
Kai
K
Harding
Heather P
HP
Scheuner
Donalyn
D
Kaufman
Randal J
RJ
Ma
Dawei
D
Coen
Donald M
DM
Ron
David
D
Yuan
Junying
J
D000818:Animals; D000943:Antigens, Differentiation; D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002934:Cinnamates / Q000494:pharmacology* / Q000633:toxicity; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D017930:Genes, Reporter; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000502:physiology; D016849:Keratitis, Herpetic / Q000188:drug therapy / Q000821:virology; D008297:Male; D008387:Marine Toxins; D051379:Mice; D010080:Oxazoles / Q000494:pharmacology / Q000633:toxicity; D016716:PC12 Cells; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D017510:Protein Folding; D011494:Protein Kinases / Q000378:metabolism; D054645:Protein Phosphatase 1; D011506:Proteins / Q000378:metabolism; D051381:Rats; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D014415:Tunicamycin / Q000494:pharmacology; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D002934:Cinnamates; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D008387:Marine Toxins; D010080:Oxazoles; D011506:Proteins; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1; C496827:salubrinal; D014415:Tunicamycin; C059041:calyculin A; D011494:Protein Kinases; D010749:Phosphoprotein Phosphatases; C513256:Ppp1r15a protein, mouse; C480350:Ppp1r15b protein, mouse; D054645:Protein Phosphatase 1; D013890:Thiourea