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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 786-795 |
| Number of pages | 10 |
| Journal | Molecular Cell |
| Volume | 56 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 18 2014 |
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ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
Cytokine-Induced GAPDH Sulfhydration Affects PSD95 Degradation and Memory. / Mir, Sajad; Sen, Tanusree; Sen, Nilkantha.
In: Molecular Cell, Vol. 56, No. 6, 18.12.2014, p. 786-795.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cytokine-Induced GAPDH Sulfhydration Affects PSD95 Degradation and Memory
AU - Mir, Sajad
AU - Sen, Tanusree
AU - Sen, Nilkantha
PY - 2014/12/18
Y1 - 2014/12/18
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2014.10.019
DO - 10.1016/j.molcel.2014.10.019
M3 - Article
VL - 56
SP - 786
EP - 795
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 6
ER -