Model: The kinase IKK may activate Htt degradation by a mammalian version of the yeast Cvt pathway

Model: The kinase IKK may activate Htt degradation by a mammalian version of the yeast Cvt pathway. The kinase IKK, activated by inflammatory stimuli, insulin signaling, DNA damage and oxidative stress pathways,,–,, Rheb and by PINK/parkin,, phosphorylates Htt S13 and activates Htt acetylation by CBP/p300 and caspase cleavage, targeting the amino-terminal fragments of Htt for degradation by the proteasome and lysosome. IKK reduces interaction of Bcl-xL/Bcl-2 with Beclin-1,,, thereby priming activation of both starvation-induced and the proposed mammalian Cvt macroautophagic pathways. IKK activates JNK1 and CBP/p300 to increase levels of p62/SQSTM1,,,,, required for the Cvt pathway and AMPK which may then activate starvation-induced macroautophagy as a compensatory feedback mechanism. Mutant Htt expression activates IKK. The proposed mammalian Cvt pathway, activated by CBP/p300 or inhibition of Sirt1 by nicotinamide, may be involved in vesicle-mediated degradation of phosphorylated/acetylated Htt N-terminal fragments by the lysosome. With aging and mutant Htt expression, the proteasome and this Cvt-like mechanism of autophagy may become impaired, and this loss of function may be compensated for by activation of starvation/rapamycin/AMPK/Sirt1-induced macroautophagy.

Publication

Does Huntingtin play a role in selective macroautophagy?. (2010) Joan S Steffan. Cell Cycle. 2010 Sep 1;9(17):3401-3413. Figure: F2. All organisms Drosophila melanogaster Homo sapiens

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