TY - JOUR
T1 - Cytokine-Induced GAPDH Sulfhydration Affects PSD95 Degradation and Memory
AU - Mir, Sajad
AU - Sen, Tanusree
AU - Sen, Nilkantha
N1 - Funding Information:
We would like to acknowledge Dr. Sylvia Smith, GRU for generously sharing cbs +/+ and cbs +/− mice with our lab and Dr. Lin Mei for his generous support and the use of his mice behavioral facility. S.M. and N.S. are supported by startup funding provided by Georgia Regents University.
Publisher Copyright:
© 2014 Elsevier Inc.
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
C2 - 25435139
AN - SCOPUS:84918823512
VL - 56
SP - 786
EP - 795
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 6
ER -