# Proteasomal Degradation of Mutant Huntingtin Exon1 Regulates Autophagy

## TL;DR

The study shows that proteasomal degradation of mutant huntingtin exon1 is linked to autophagy, revealing a new mechanism of cytotoxicity in Huntington’s disease.

## Contribution

The study reveals that proteasomal degradation of mHttEx1 regulates IBophagy, a selective autophagy pathway for misfolded protein aggregates.

## Key findings

- Yeast mutants with defective proteasomal degradation of mHttEx1 show impaired IBophagy.
- Cdc48 Ubx cofactors are essential for both proteasomal degradation of mHttEx1 and IBophagy.
- Inhibiting the proteasome in yeast cells eliminates IBophagy.

## Abstract

What are the main findings?
Yeast mutants defective in proteasomal degradation of soluble mutant huntingtin exon1 (mHttEx1) display impaired IBophagy, a selective autophagy pathway for misfolded protein inclusion bodies.Specific Cdc48 Ubx cofactors are required for efficient proteasomal degradation of mHttEx1 and IBophagy.Inhibition of proteasome function in yeast cells abolishes IBophagy.

Yeast mutants defective in proteasomal degradation of soluble mutant huntingtin exon1 (mHttEx1) display impaired IBophagy, a selective autophagy pathway for misfolded protein inclusion bodies.

Specific Cdc48 Ubx cofactors are required for efficient proteasomal degradation of mHttEx1 and IBophagy.

Inhibition of proteasome function in yeast cells abolishes IBophagy.

What is the implication of the main finding?
The strong correlation between proteasomal degradation of soluble mHttEx1 and IBophagy indicates the negative role of mHttEx1 in autophagy.Our finding that IBophagy depends on the degradation of soluble mHttEx1 may represent an additional mechanism underlying mHttEx1-induced cytotoxicity.

The strong correlation between proteasomal degradation of soluble mHttEx1 and IBophagy indicates the negative role of mHttEx1 in autophagy.

Our finding that IBophagy depends on the degradation of soluble mHttEx1 may represent an additional mechanism underlying mHttEx1-induced cytotoxicity.

Accumulation of misfolded proteins is implicated in neurodegenerative diseases. One of these is Huntington’s disease, which is caused by an expansion of trinucleotide (CAG) repeats in exon 1 of huntingtin gene (HTT). This expansion results in the production of mutant huntingtin exon1 protein (mHttEx1) containing polyglutamine tracks that is prone to cytotoxic aggregation. These mHttEx1 aggregates range from small soluble aggregates to large insoluble inclusion bodies. The mechanisms to clear mHttEx1 aggregates include ubiquitin-dependent proteasomal degradation and autophagy. For the proteasomal degradation of mHttEx1, ubiquitinated protein is first recognized by the Cdc48 complex for extraction and unfolding. For autophagy, mHttEx1 inclusion bodies are engulfed by an autophagosome, which fuses with the vacuole/lysosome and delivers cargo for vacuolar degradation. We name this autophagy IBophagy. In this study, we further show that the ubiquitination of mHttEx1 by the E3 ligase San1, its extraction and unfolding by the Cdc48 complex, and subsequent proteasomal degradation are all essential steps for mHttEx1 IBophagy in budding yeast, revealing a new layer of autophagy regulation and mHttEx1 cytotoxicity.