Cytokine-induced GAPDH sulfhydration affects PSD95 degradation and memory

Mol Cell. 2014 Dec 18;56(6):786-95. doi: 10.1016/j.molcel.2014.10.019. Epub 2014 Nov 26.

Abstract

Induction of a proinflammatory cytokine, interleukin-1β (IL-1β) plays a role in memory impairment associated with various neurological disorders and brain injury. Here we show that IL-1β-induced memory impairment in brain is mediated by hydrogen sulfide (H2S) synthesized by cystathionine beta-synthase (CBS). H2S modifies GAPDH essentially via sulfhydration in dendrites, which promotes its binding to the E3 ligase protein, Siah. Then Siah binds to a critical synaptic scaffolding molecule, PSD95, and leads it to degradation via ubiquitination. In CBS heterozygous mice (cbs(+/-)) and primary neurons depleted with either CBS or IL-1R, IL-1β-induced loss of PSD95 was rescued along with a decrease in the level of GAPDH sulfhydration. Moreover, decrease in the loss of PSD95 in cbs(+/-) mice results in improvement of IL-1β-induced cognitive deficits and neurobehavioral outcomes. Thus, our findings reveal a mechanism where GAPDH sulfhydration appears to be a physiologic determinant of cytokine-induced memory impairment in brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cystathionine beta-Synthase / metabolism
  • Disks Large Homolog 4 Protein
  • Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism*
  • Guanylate Kinases / metabolism*
  • HEK293 Cells
  • Humans
  • Hydrogen Sulfide / metabolism
  • Interleukin-1beta / physiology*
  • Male
  • Membrane Proteins / metabolism*
  • Memory Disorders / enzymology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Protein Processing, Post-Translational
  • Proteolysis
  • Synapses / enzymology
  • Synapses / pathology

Substances

  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Interleukin-1beta
  • Membrane Proteins
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • Guanylate Kinases
  • Cystathionine beta-Synthase
  • Hydrogen Sulfide