title: Cytokine-induced GAPDH sulfhydration affects PSD95 degradation and memory.
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.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Sajad
authors.initials: S
authors.lastname: Mir
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Tanusree
authors.initials: T
authors.lastname: Sen
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: nsen@gru.edu.
authors.forename: Nilkantha
authors.initials: N
authors.lastname: Sen
mesh_terms: D000818:Animals; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D051528:Guanylate Kinases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism; D053583:Interleukin-1beta / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008569:Memory Disorders / Q000201:enzymology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D013569:Synapses / Q000201:enzymology / Q000473:pathology
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D053583:Interleukin-1beta; D008565:Membrane Proteins; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D051528:Guanylate Kinases; D003541:Cystathionine beta-Synthase; D006862:Hydrogen Sulfide