Nitric oxide triggers the assembly of "type II" stress granules linked to decreased cell viability

Cell Death Dis. 2018 Nov 13;9(11):1129. doi: 10.1038/s41419-018-1173-x.

Abstract

We show that 3-morpholinosydnonimine (SIN-1)-induced nitric oxide (NO) triggers the formation of SGs. Whereas the composition of NO-induced SGs is initially similar to sodium arsenite (SA)-induced type I (cytoprotective) SGs, the progressive loss of eIF3 over time converts them into pro-death (type II) SGs. NO-induced SG assembly requires the phosphorylation of eIF2α, but the transition to type II SGs is temporally linked to the mTOR-regulated displacement of eIF4F complexes from the m7 guanine cap. Whereas SA does not affect mitochondrial morphology or function, NO alters mitochondrial integrity and function, resulting in increased ROS production, decreased cytoplasmic ATP, and plasma membrane permeabilization, all of which are supported by type II SG assembly. Thus, cellular energy balance is linked to the composition and function of NO-induced SGs in ways that determine whether cells live or die.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / metabolism
  • Arsenites / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cytoplasmic Granules / drug effects*
  • Cytoplasmic Granules / metabolism
  • Cytoplasmic Granules / ultrastructure
  • Eukaryotic Initiation Factor-2 / genetics
  • Eukaryotic Initiation Factor-2 / metabolism
  • Eukaryotic Initiation Factor-3 / genetics
  • Eukaryotic Initiation Factor-3 / metabolism
  • Eukaryotic Initiation Factor-4F / genetics
  • Eukaryotic Initiation Factor-4F / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Molsidomine / analogs & derivatives
  • Molsidomine / metabolism
  • Molsidomine / pharmacology
  • Nitric Oxide / metabolism*
  • Nitric Oxide Donors / metabolism
  • Nitric Oxide Donors / pharmacology
  • Osteoblasts / cytology
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Protein Biosynthesis
  • Reactive Oxygen Species / metabolism
  • Sodium Compounds / pharmacology
  • Stress, Physiological
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Arsenites
  • Eukaryotic Initiation Factor-2
  • Eukaryotic Initiation Factor-3
  • Eukaryotic Initiation Factor-4F
  • Nitric Oxide Donors
  • Reactive Oxygen Species
  • Sodium Compounds
  • Nitric Oxide
  • sodium arsenite
  • linsidomine
  • Adenosine Triphosphate
  • Molsidomine
  • MTOR protein, human
  • TOR Serine-Threonine Kinases