# UXT oligomerization is essential for its role as an autophagy adaptor

## TL;DR

UXT forms a hexamer and higher-order structures that help clear protein aggregates through autophagy.

## Contribution

UXT's high-order oligomerization is essential for its role in autophagy, distinguishing it from similar proteins like prefoldin.

## Key findings

- UXT can form a hexamer that binds misfolded proteins.
- Hexamers assemble into high-order oligomers via β hairpins.
- UXT oligomerization is crucial for clearing SOD1(A4V) aggregates.

## Abstract

SQSTM1/p62 serves as an autophagy receptor that binds to ubiquitinated misfolded proteins and delivers them to the phagophores for removal. This function can be augmented by autophagy adaptors, such as UXT. Here, by in silico structural homology modeling, we demonstrated that UXT can potentially form a hexameric structure to bind to misfolded proteins. Importantly, the UXT hexamer can assemble into a high-order oligomer via β hairpins positioned outside of each hexamer, facilitating the formation and efficient removal of protein aggregates. Consistently, the high-order oligomer of UXT was found to be essential for inducing the efficient clearance of SOD1(A4V) aggregates, in both in vitro and in vivo. Collectively, our research emphasizes the crucial importance of UXT oligomerization in its role as an autophagy adaptor and explains why the structurally and functionally similar prefoldin, which lacks such high-order oligomerization capacity, is employed for the refolding of individual misfolded proteins, but not autophagy.

•UXT can form a hexamer capable of binding to misfolded proteins•UXT hexamers can assemble into a high-order oligomer via extra β hairpins•The high-order oligomerization of UXT is crucial for removal of protein aggregates

UXT can form a hexamer capable of binding to misfolded proteins

UXT hexamers can assemble into a high-order oligomer via extra β hairpins

The high-order oligomerization of UXT is crucial for removal of protein aggregates

Biochemistry; Molecular biology