Results: 2

Figure 1

Figure 1. From: Does Huntingtin play a role in selective macroautophagy?.

Htt may have evolved from Cvt proteins Atg23, Vac8 and Atg11. (A) The yeast Vac8 protein contains 11 armadillo repeats which can be described as ancestral HEAT repeats. Throughout evolution, Vac8 may have fused with yeast protein Atg23 on the amino-terminus and Atg11 on the C-terminus. These yeast proteins are essential for the cytoplasm to vacuole targeting (Cvt) selective autophagic pathway, which is activated by TORC1 in yeast grown under nutrient-rich conditions. The cartoon is not drawn to scale. (B) A protein complex essential for the yeast Cvt pathway may be similar to a hypothetical human complex required for selective macroautophagy under nutrient-rich conditions.

Joan S Steffan. Cell Cycle. 2010 September 1;9(17):3401-3413.
Figure 2

Figure 2. From: Does Huntingtin play a role in selective macroautophagy?.

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,48,118–120,153,154 Rheb155 and by PINK/parkin,146,147 phosphorylates Htt S13 and activates Htt acetylation by CBP/p300 and caspase cleavage,13 targeting the amino-terminal fragments of Htt for degradation by the proteasome and lysosome.1 IKK reduces interaction of Bcl-xL/Bcl-2 with Beclin-1,4,13,148 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/SQSTM1,4,8,43,148,149 required for the Cvt pathway and AMPK4 which may then activate starvation-induced macroautophagy as a compensatory feedback mechanism. Mutant Htt expression activates IKK.2 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.

Joan S Steffan. Cell Cycle. 2010 September 1;9(17):3401-3413.

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