TY - JOUR
T1 - Selective inhibition of mitochondrial JNK signaling achieved using peptide mimicry of the sab kinase interacting motif-1 (KIM1)
AU - Chambers, Jeremy W.
AU - Cherry, Lisa
AU - Laughlin, John D.
AU - Figuera-Losada, Mariana
AU - Lograsso, Philip V.
PY - 2011/8/19
Y1 - 2011/8/19
N2 - The c-jun N-terminal kinases (JNKs) are responsive to stress stimuli leading to activation of proapoptotic proteins and transcription. Additionally, JNK mitochondrial localization has been reported. To selectively target mitochondrial JNK signaling, we exploited JNK interaction with its mitochondrial scaffold, Sab, using small interfering RNAs (siRNAs) and a cell-permeable peptide corresponding to the KIM1 domain of Sab. Gene silencing and peptide interference of this interaction disrupted JNK translocation to the mitochondria and reduced phosphorylation of Bcl-2 without significant impact on c-Jun phosphorylation or AP-1 transcription. In contrast, the JNK inhibitory peptide (TI-JIP1) prevented these three functions. Tat-Sab KIM1 selectivity was also demonstrated in anisomycin-stressed HeLa cells where Tat-Sab KIM1 prevented Bcl-2 phosphorylation, cell death, loss of mitochondrial membrane potential, and superoxide generation but not c-Jun phosphorylation. Conversely, TI-JIP1 prevented all aforementioned stress-induced events. This probe introduces a means to evaluate JNK-mediated events on the mitochondria without intervening in nuclear functions of JNK.
AB - The c-jun N-terminal kinases (JNKs) are responsive to stress stimuli leading to activation of proapoptotic proteins and transcription. Additionally, JNK mitochondrial localization has been reported. To selectively target mitochondrial JNK signaling, we exploited JNK interaction with its mitochondrial scaffold, Sab, using small interfering RNAs (siRNAs) and a cell-permeable peptide corresponding to the KIM1 domain of Sab. Gene silencing and peptide interference of this interaction disrupted JNK translocation to the mitochondria and reduced phosphorylation of Bcl-2 without significant impact on c-Jun phosphorylation or AP-1 transcription. In contrast, the JNK inhibitory peptide (TI-JIP1) prevented these three functions. Tat-Sab KIM1 selectivity was also demonstrated in anisomycin-stressed HeLa cells where Tat-Sab KIM1 prevented Bcl-2 phosphorylation, cell death, loss of mitochondrial membrane potential, and superoxide generation but not c-Jun phosphorylation. Conversely, TI-JIP1 prevented all aforementioned stress-induced events. This probe introduces a means to evaluate JNK-mediated events on the mitochondria without intervening in nuclear functions of JNK.
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U2 - 10.1021/cb200062a
DO - 10.1021/cb200062a
M3 - Article
C2 - 21563797
AN - SCOPUS:80051999961
SN - 1554-8929
VL - 6
SP - 808
EP - 818
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 8
ER -