S-Nitrosylation of Bcl-2 Inhibits Its Ubiquitin-Proteasomal Degradation

Bcl-2 is a key apoptosis regulatory protein of the mitochondrial death pathway whose function is dependent on its expression levels. Although Bcl-2 expression is controlled by various mechanisms, post-translational modifications, such as ubiquitination and proteasomal degradation, have emerged as important regulators of Bcl-2 function. However, the underlying mechanisms of this regulation are unclear. We report here that Bcl-2 undergoes S-nitrosylation by endogenous nitric oxide (NO) in response to multiple and that this of of by the and by S-nitrosylation of its and death by the and of on Bcl-2 to of its of Bcl-2 that the of Bcl-2 and are important in the S-nitrosylation and that of Bcl-2 of the and Bcl-2 that this is a that Bcl-2 and function various a function of and its regulation of a key the of death and Bcl-2 is a key apoptosis regulatory protein of the mitochondrial death pathway whose function is dependent on its expression levels. Although Bcl-2 expression is controlled by various mechanisms, post-translational modifications, such as ubiquitination and proteasomal degradation, have emerged as important regulators of Bcl-2 function. However, the underlying mechanisms of this regulation are unclear. We report here that Bcl-2 undergoes S-nitrosylation by endogenous nitric oxide (NO) in response to multiple and that this of of by the and by S-nitrosylation of its and death by the and of on Bcl-2 to of its of Bcl-2 that the of Bcl-2 and are important in the S-nitrosylation and that of Bcl-2 of the and Bcl-2 that this is a that Bcl-2 and function various a function of and its regulation of a key the of death and Bcl-2 is a key protein of the mitochondrial death pathway of such as of and regulation of mitochondrial are of the mechanisms by Bcl-2 its of Bcl-2 protein is is in of of and of its expression to in and Bcl-2 expression is by various mechanisms, post-translational and Bcl-2 is the is a protein in oxide (NO) nitric nitric is important in a by in its of a of apoptosis to have a and on a of the of of the and the and of that a of to apoptosis death protein and of a of mechanisms, such as of of and of Bcl-2 and of the of the mechanisms by the function of various is S-nitrosylation post-translational of various and the function of and protein and and S-nitrosylation of this to the of in the regulation of Bcl-2 function in apoptosis of is a that as by the on to in various is in and of in death by apoptosis and its regulation the of and such as and have in apoptosis and However, the mechanisms in the regulation of apoptosis in response to of Bcl-2 and have in the that Bcl-2 a key by Bcl-2 S-nitrosylation of the to death and of Bcl-2 its the the of and in S-nitrosylation and ubiquitination of the of a of regulation of Bcl-2 that important in apoptosis and the of by and and the in and in and and and the and and the apoptosis and protein and and the and Bcl-2 by of Bcl-2 and by and expression of by to the of in of by of Bcl-2 of Bcl-2 by in of and of of Bcl-2 to the in the of the the and and by of Bcl-2 and in and by the and are by the the to the of protein and in a of and the and of and by the and the of by by and the in and a and a the as and by its of and of the a 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is to and to the report the of to in and this by the is the of that by the and its levels. the of by the and the of in the regulation of of on levels. and of in the the and by as the the response of of of of by the as and of the in and by are is a key protein of the mitochondrial death pathway this protein is in the regulation of to mitochondrial Bcl-2 and on apoptosis by that of Bcl-2 apoptosis a as the of the in Bcl-2 protein expression in the in the the of Bcl-2 as a of apoptosis and the of the mitochondrial pathway in death to Bcl-2 of and apoptosis by are of Bcl-2 expression in and as a of on Bcl-2 the of Bcl-2 in the regulation of Bcl-2 by in of on Bcl-2 expression in by that of the a in the expression of that this of the and the in the of various and and the expression of Bcl-2 that the and the of Bcl-2 by the and this and the Bcl-2 expression the of and as on Bcl-2 of on Bcl-2 of and and Bcl-2 by various and Bcl-2 expression to of by and to the in in the of are of on Bcl-2 expression and of the and and and Bcl-2 expression by and and and Bcl-2 expression by Bcl-2 in the Bcl-2 and to the of Bcl-2 and the are have that Bcl-2 is by proteasomal Bcl-2 by is by this a and its on Bcl-2 by in that Bcl-2 by a of of Bcl-2 by by the that Bcl-2 by of on Bcl-2 that Bcl-2 a in Bcl-2 that its and function of Bcl-2 and to its and is the of Bcl-2 that Bcl-2 degradation, the of on Bcl-2 in the of various and on Bcl-2 by Bcl-2 that on Bcl-2 and and on the the of Bcl-2 a in Bcl-2 in the that Bcl-2 a that is of its of the by Bcl-2 degradation, ubiquitination of Bcl-2 in response to by in the of and and ubiquitination by that to ubiquitination of Bcl-2 and that and this and Bcl-2 the of in of Bcl-2 by of on Bcl-2 of Bcl-2 the the the in the of to Bcl-2 and the by of ubiquitination to are of Bcl-2 the function of by S-nitrosylation Bcl-2 and this Bcl-2 the of on Bcl-2 and and and by and by and that of the S-nitrosylation of and this by and and this that its to the ubiquitination and Bcl-2 by the this a of and its on Bcl-2 S-nitrosylation and ubiquitination that to S-nitrosylation of Bcl-2 the of and on Bcl-2 ubiquitination in that S-nitrosylation a key by to ubiquitination and of Bcl-2 by the of on S-nitrosylation and ubiquitination of of on Bcl-2 S-nitrosylation in by of Bcl-2 and by to the the S-nitrosylation of Bcl-2 by and Bcl-2 of and on Bcl-2 Bcl-2 the in the of and the Bcl-2 and are that by S-nitrosylation of that the on Bcl-2 ubiquitination is to its in the and of and its on and and and by that on proteasomal as that this is to and S-nitrosylation of of Bcl-2 S-nitrosylation of Bcl-2 a the of and on Bcl-2 that S-nitrosylation of Bcl-2 that this is a that the function of of on Bcl-2 of Bcl-2 and by to the of the are and Bcl-2 Bcl-2 S-nitrosylation and to the that in the Bcl-2 the in Bcl-2 and the Bcl-2 by and and Bcl-2 by that of the S-nitrosylation of by that S-nitrosylation in response to is the of Bcl-2 S-nitrosylation of Bcl-2 the protein and its degradation, the of on Bcl-2 the and as and by that to ubiquitination of Bcl-2 by that S-nitrosylation of the protein its ubiquitination and of on S-nitrosylation and ubiquitination of Bcl-2 the and by to the of the as and by are have that of Bcl-2 to death by various is important of to in its in the regulation of Bcl-2 and the underlying mechanisms the that Bcl-2 protein S-nitrosylation and that this the its function. of Bcl-2 in the that by in death and of and this and the death and and the of and its regulation of Bcl-2 in the that of mitochondrial this that mitochondrial and death of apoptosis by the a mitochondrial death pathway is by apoptosis by mitochondrial that Bcl-2 apoptosis the of the mitochondrial death pathway in function of Bcl-2 is its expression levels. 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on Bcl-2 that of this its and function. the of to S-nitrosylation of Bcl-2 to of a and the of on the in the of We that on proteasomal as the on Bcl-2 to S-nitrosylation of have in proteasomal that the of on Bcl-2 to S-nitrosylation of by in the of Bcl-2 and to in a of Bcl-2 S-nitrosylation by of the that this is the of Bcl-2 to that S-nitrosylation of Bcl-2 its ubiquitination and this a of Bcl-2 regulation by the of this by the and is that of in apoptosis is a death that is to apoptosis the death pathway We that Bcl-2 in response to that S-nitrosylation is a that Bcl-2 and function various that important as a of death the mitochondrial pathway by Bcl-2 and function. this its to the protein and its ubiquitination and proteasomal of Bcl-2 to a that its various S-nitrosylation of a of regulation that Bcl-2 and important that and and Bcl-2 expression have of the key regulators of death and its to on the function of on Bcl-2 regulation have important in and its Bcl-2 is a key protein of the mitochondrial death pathway of such as of and regulation of mitochondrial are of the mechanisms by Bcl-2 its of Bcl-2 protein is is in of of and of its expression to in and Bcl-2 expression is by various mechanisms, post-translational and Bcl-2 is the is a protein in oxide (NO) nitric nitric is important in a by in its of a of apoptosis to have a and on a of the of of the and the and of that a of to apoptosis death protein and of a of mechanisms, such as of of and of Bcl-2 and of the of the mechanisms by the function of various is S-nitrosylation post-translational of various and the function of and protein and and S-nitrosylation of this to the of in the regulation of Bcl-2 function in apoptosis of is a that as by the on to in various is in and of in death by apoptosis and its regulation the of and such as and have in apoptosis and However, the mechanisms in the regulation of apoptosis in response to unclear. of Bcl-2 and have in the that Bcl-2 a key by Bcl-2 S-nitrosylation of the to 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pathway by and the of the the of in the regulation of in the of various and and apoptosis by and that and death by and this in a that the and the and the of on that in of on a the response and by the the of on the and that the and by the and this of in the of is to and to the report the of to in and this by the is the of that by the and its levels. the of by the and the of in the regulation of of on levels. and of in the the and by as the the response of of of of by the as and of the in and by are is a key protein of the mitochondrial death pathway this protein is in the regulation of to mitochondrial Bcl-2 and on apoptosis by that of Bcl-2 apoptosis a as the of the in Bcl-2 protein expression in the in the the of Bcl-2 as a of apoptosis and the of the mitochondrial pathway in death to Bcl-2 of and apoptosis by are of Bcl-2 expression in and as a of on Bcl-2 the of Bcl-2 in the regulation of Bcl-2 by in of on Bcl-2 expression in by that of the a in the expression of that this of the 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the the the in the of to Bcl-2 and the by of ubiquitination to are of Bcl-2 the function of by S-nitrosylation Bcl-2 and this Bcl-2 the of on Bcl-2 and and and by and by and that of the S-nitrosylation of and this by and and this that its to the ubiquitination and Bcl-2 by the this a of and its on Bcl-2 S-nitrosylation and ubiquitination that to S-nitrosylation of Bcl-2 the of and on Bcl-2 ubiquitination in that S-nitrosylation a key by to ubiquitination and of Bcl-2 by the of on S-nitrosylation and ubiquitination of of on Bcl-2 S-nitrosylation in by of Bcl-2 and by to the the S-nitrosylation of Bcl-2 by and Bcl-2 of and on Bcl-2 Bcl-2 the in the of and the Bcl-2 and are that by S-nitrosylation of that the on Bcl-2 ubiquitination is to its in the and of and its on and and and by that on proteasomal as that this is to and S-nitrosylation of of Bcl-2 S-nitrosylation of Bcl-2 a the of and on Bcl-2 that S-nitrosylation of Bcl-2 that this is a that the function of of on Bcl-2 of Bcl-2 and 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that the and by the and this of in the of is to and to the report the of to in and this by the is the of that by the and its levels. the of by the and the of in the regulation of Bcl-2 is a key protein of the mitochondrial death pathway this protein is in the regulation of to mitochondrial Bcl-2 and on apoptosis by that of Bcl-2 apoptosis a as the of the in Bcl-2 protein expression in the in the the of Bcl-2 as a of apoptosis and the of the mitochondrial pathway in of on Bcl-2 the of Bcl-2 in the regulation of Bcl-2 by in of on Bcl-2 expression in by that of the a in the expression of that this of the and the in the of various and and the expression of Bcl-2 that the and the of Bcl-2 by the and this and the Bcl-2 expression the of and as on Bcl-2 have that Bcl-2 is by proteasomal Bcl-2 by is by this a and its on Bcl-2 by in that Bcl-2 by a of of Bcl-2 by by the that Bcl-2 by of on Bcl-2 that Bcl-2 a in Bcl-2 that its and function of Bcl-2 and to its and is the of Bcl-2 that Bcl-2 degradation, the of on Bcl-2 in the of various and on Bcl-2 by Bcl-2 that on Bcl-2 and and on the the of Bcl-2 a in Bcl-2 in the that Bcl-2 a that is of its of the by Bcl-2 degradation, ubiquitination of Bcl-2 in response to by in the of and and ubiquitination by that to ubiquitination of Bcl-2 and that and this and Bcl-2 the of in of Bcl-2 by of Bcl-2 the function of by S-nitrosylation Bcl-2 and this Bcl-2 the of on Bcl-2 and and and by and by and that of the S-nitrosylation of and this by and and this that its to the ubiquitination and Bcl-2 by the this a of and its on Bcl-2 S-nitrosylation and ubiquitination that to S-nitrosylation of Bcl-2 the of and on Bcl-2 ubiquitination in that S-nitrosylation a key by to ubiquitination and of Bcl-2 by the that by S-nitrosylation of that the on Bcl-2 ubiquitination is to its in the and of and its on and and and by that on proteasomal as that this is to and S-nitrosylation of of Bcl-2 S-nitrosylation of Bcl-2 a the of and on Bcl-2 that S-nitrosylation of Bcl-2 that this is a that the function of and Bcl-2 Bcl-2 S-nitrosylation and to the that in the Bcl-2 the in Bcl-2 and the Bcl-2 by and and Bcl-2 by that of the S-nitrosylation of by that S-nitrosylation in response to is the of Bcl-2 S-nitrosylation of Bcl-2 the protein and its degradation, the of on Bcl-2 the and as and by that to ubiquitination of Bcl-2 by that S-nitrosylation of the protein its ubiquitination and have that of Bcl-2 to death by various is important of to in its in the regulation of Bcl-2 and the underlying mechanisms the that Bcl-2 protein S-nitrosylation and that this the its function. of Bcl-2 in the that by in death and of and this and the death and and the of and its regulation of Bcl-2 in the that of mitochondrial this that mitochondrial and death of apoptosis by the a mitochondrial death pathway is by apoptosis by mitochondrial that Bcl-2 apoptosis the of the mitochondrial death pathway in function of Bcl-2 is its expression levels. Although Bcl-2 expression is controlled by various mechanisms, post-translational modifications, such as ubiquitination and have emerged as important regulators of Bcl-2 function that of Bcl-2 by in Bcl-2 ubiquitination and proteasomal and of the and to Bcl-2 the of the proteasomal pathway in Bcl-2 and Bcl-2 ubiquitination by the and this that Bcl-2 by its the that Bcl-2 is by and and in response to such as is the of Bcl-2 of Bcl-2 in the of on Bcl-2 However, that on Bcl-2 that Bcl-2 a that Bcl-2 is a death that apoptosis the death death the mitochondrial its of Bcl-2 regulation that of Bcl-2 a Bcl-2 ubiquitination and that mechanisms of Bcl-2 regulation and are by by Bcl-2 ubiquitination is S-nitrosylation of the its and of by the of such as and to apoptosis the of on Bcl-2 ubiquitination and degradation, S-nitrosylation of Bcl-2 in We that S-nitrosylation of Bcl-2 and that this by the and and by the and of S-nitrosylation by the the of on Bcl-2 ubiquitination the of S-nitrosylation on Bcl-2 that of this its and function. the of to S-nitrosylation of Bcl-2 to of a and the of on the in the of We that on proteasomal as the on Bcl-2 to S-nitrosylation of have in proteasomal that the of on Bcl-2 to S-nitrosylation of by in the of Bcl-2 and to in a of Bcl-2 S-nitrosylation by of the that this is the of Bcl-2 to that S-nitrosylation of Bcl-2 its ubiquitination and this a of Bcl-2 regulation by the of this by the and is that of in apoptosis is a death that is to apoptosis the death pathway We that Bcl-2 in response to that S-nitrosylation is a that Bcl-2 and function various that important as a of death the mitochondrial pathway by Bcl-2 and function. this its to the protein and its ubiquitination and proteasomal of Bcl-2 to a that its various S-nitrosylation of a of regulation that Bcl-2 and important that and and Bcl-2 expression have of the key regulators of death and its to on the function of on Bcl-2 regulation have important in and its have that of Bcl-2 to death by various is important of to in its in the regulation of Bcl-2 and the underlying mechanisms the that Bcl-2 protein S-nitrosylation and that this the its function. of Bcl-2 in the that by in death and of and this and the death and and the of and its regulation of Bcl-2 in the that of mitochondrial this that mitochondrial and death of apoptosis by the a mitochondrial death pathway is by apoptosis by mitochondrial that Bcl-2 apoptosis the of the mitochondrial death pathway in function of Bcl-2 is its expression levels. Although Bcl-2 expression is controlled by various mechanisms, post-translational modifications, such as ubiquitination and have emerged as important regulators of Bcl-2 function that of Bcl-2 by in Bcl-2 ubiquitination and proteasomal and of the and to Bcl-2 the of the proteasomal pathway in Bcl-2 and Bcl-2 ubiquitination by the and this that Bcl-2 by its the that Bcl-2 is by and and in response to such as is the of Bcl-2 of Bcl-2 in the of on Bcl-2 However, that on Bcl-2 that Bcl-2 a that Bcl-2 is a death that apoptosis the death death the mitochondrial its of Bcl-2 regulation that of Bcl-2 a Bcl-2 ubiquitination and that mechanisms of Bcl-2 regulation and are by by Bcl-2 ubiquitination is S-nitrosylation of the its and of by the of such as and to apoptosis the of on Bcl-2 ubiquitination and degradation, S-nitrosylation of Bcl-2 in We that S-nitrosylation of Bcl-2 and that this by the and and by the and of S-nitrosylation by the the of on Bcl-2 ubiquitination the of S-nitrosylation on Bcl-2 that of this its and function. the of to S-nitrosylation of Bcl-2 to of a and the of on the in the of We that on proteasomal as the on Bcl-2 to S-nitrosylation of have in proteasomal that the of on Bcl-2 to S-nitrosylation of by in the of Bcl-2 and to in a of Bcl-2 S-nitrosylation by of the that this is the of Bcl-2 to that S-nitrosylation of Bcl-2 its ubiquitination and this a of Bcl-2 regulation by the of this by the and is that of in apoptosis is a death that is to apoptosis the death pathway We that Bcl-2 in response to that S-nitrosylation is a that Bcl-2 and function various that important as a of death the mitochondrial pathway by Bcl-2 and function. this its to the protein and its ubiquitination and proteasomal of Bcl-2 to a that its various S-nitrosylation of a of regulation that Bcl-2 and important that and and Bcl-2 expression have of the key regulators of death and its to on the function of on Bcl-2 regulation have important in and its