Sp1-CSE-H2S pathway plays an important role in homocysteine-metabolism, whose disorder can cause hyperhomocysteinemia. H2S deficiency in hyperhomocysteinemia has been reported but it's unclear whether this deficiency affects hyperhomocysteinemia. Furthermore, it's unknown whether the post-translational modification of Sp1-CSE can affect hyperhomocysteinemia. We detected the post-translational modification of Sp1-CSE-H2S pathway and revealed four major findings: (1) the accumulation of homocysteine augmented the nitration of CSE, blunted its bio-activity and caused H2S deficiency. (2) H2S deficiency lowered the S-sulfhydration of Sp1, inhibited its transcriptional activity, resulted in lower expression of CSE. CSE deficiency decreased H2S level further, which in turn lowered the S-sulfhydration level of CSE. (3) CSE was S-sulfhydrated at Cys84, Cys109, Cys172, Cys229, Cys252, Cys307 and Cys310 under physiological conditions, mutation of Cys84, Cys109, Cys229, Cys252 and Cys307 decreased its S-sulfhydration level and bio-activity. (4) H2S deficiency could trap hyperhomocysteinemia into a progressive vicious circle, while blocking nitration or restoring S-sulfhydration could break this circle. This study reveals a novel mechanism involved in the disorder of Hcy-metabolism, which may provide a candidate therapeutic strategy for hyperhomocysteinemia.
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