Work

A localization gate licenses chaperone-mediated autophagy of SNAI (snail) to restrain epithelial-mesenchymal transition competence in breast cancer

Year: 2026

Type: article

Abstract: SNAI (snail family transcriptional repressor) is a master regulator of epithelial-mesenchymal transition (EMT), yet its protein abundance varies markedly across breast cancer subtypes and cellular states. We identify SNAI as a bona fide substrate of chaperone-mediated autophagy (CMA) and propose a localization gate model in which nucleocytoplasmic trafficking dictates CMA accessibility. Macroautophagy inhibition stabilizes SQSTM1/p62 but does not alter SNAI levels, whereas depletion of the CMA chaperone HSPA8/HSC70 or the lysosomal receptor LAMP2A increases SNAI protein levels and extends its half-life. A CMA-resistant SNAI mutant fails to bind HSPA8-LAMP2A, is stabilized, and enhances EMT outputs, including migration, invasion, and lung colonization. In triple-negative breast cancer cells, SNAI is predominantly nuclear at baseline and thus inaccessible to CMA. Serum starvation promotes nuclear export, enabling cytosolic exposure and CMA-dependent degradation, which is blocked by leptomycin B. These findings connect selective autophagy to compartmental shielding and suggest that promoting cytosolic exposure and/or enhancing CMA capacity may attenuate SNAI-driven EMT competence.

Source: Autophagy

DOI: 10.1080/15548627.2026.2646240

Authors: Ki-Jun Ryu, Minju Kim, Jiyun Yoo

Institution: Gyeongsang National University

Language: English

Topic: Autophagy in Disease and Therapy

Subfield: Epidemiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funder: National Research Foundation of Korea