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Activation of pro-survival autophagy by a small molecule promoting p62 oligomerisation

Lookup NU author(s): Dr Johan PanekORCiD, Dr Edward FielderORCiD, Steph Crabtree, Dr Tetsushi Kataura, Niall Wilson, Lakshana Baheerathan, Jiangyu Tang, Laura BoothORCiD, Professor Wyatt YueORCiD, Professor Gavin RichardsonORCiD, Professor Viktor KorolchukORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

Autophagy is a critical mechanism of cellular quality control, orchestrated by selective autophagy receptor (SAR) proteins. Pharmacologically enhancing the cargo-targeting capacity of SARs presents an attractive but underexplored strategy for the precise therapeutic activation of autophagy. Here, we characterize SQ-1, a small-molecule activator of autophagy that engages the prototypical SAR protein p62/sequestosome-1 (SQSTM1). We show that SQ-1 sensitizes p62 to oxidation and promotes its disulfide-mediated oligomerization in response to mitochondrial reactive oxygen species (ROS). This ROS-dependent activation of p62-mediated selective autophagy enhances the clearance of ROS-generating mitochondria and restores cell viability in models of Niemann-Pick type C1 disease, which is marked by impaired autophagic flux. In summary, the unique mode of action of SQ-1 enables self-regulated autophagy activation, offering a potential therapeutic strategy for lysosomal storage disorders and a broader spectrum of age-related diseases characterized by defective autophagy.

Publication metadata

Author(s): Panek P, Fielder E, Sun C, Crabtree S, Kataura T, Wilson N, Baheerathan L, Tang J, Booth L, Yue W, Richardson GD, Holder L, Miller GJ, Reynisson J, Sarkar S, Korolchuk VI

Publication type: Article

Publication status: Published

Journal: Journal of Biological Chemistry

Year: 2026

Volume: 302

Issue: 10

Print publication date: 01/10/2026

Online publication date: 11/08/2026

Acceptance date: 04/08/2026

Date deposited: 08/09/2026

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: ScienceDirect

URL: https://doi.org/10.1016/j.jbc.2026.113430

DOI: 10.1016/j.jbc.2026.113430

Data Access Statement: Original images of immunoblotting are provided as supplementary material. All other datasets generated in this study are presented and analyzed within this article and are avail able from the corresponding author upon request.

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