Inhibition of ESCRT-III activates alternative pathways for protein degradation and secretion

Apr 4, 2026Neurochemistry international

Blocking ESCRT-III triggers alternative ways cells break down and release proteins

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Abstract

ESCRT-III dysfunction is associated with suppressed macroautophagy but enhanced protein clearance in various cell types.

Mutations in ESCRT-III components like CHMP2B and VPS4A/B are linked to neurological disorders such as frontotemporal lobar degeneration.
Despite reduced macroautophagic activity, protein clearance was promoted in cell types including Neuro2a cells with ESCRT-III dysfunction.
The clearance process was confirmed to occur independently of macroautophagy in ATG13-or ATG5-knockout cells.
Imaging showed increased accumulation of substrate proteins in lysosomes, indicating activation of a microautophagy-like pathway.
Inhibition of ESCRT-III also led to enhanced secretion of proteins independent of extracellular vesicles.
Cell-to-cell transmission of aggregated tau was further promoted by the inhibition of ESCRT-III.

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Mutations in components of the endosomal sorting complex required for transport (ESCRT)-III, such as CHMP2B and VPS4A/B, are known to cause neurological disorders, including frontotemporal lobar degeneration (FTLD) and developmental encephalopathies. Although ESCRT complexes are required for macroautophagy and for certain forms of microautophagy, the effects of ESCRT-III dysfunction on intracellular protein degradation remain unclear. In this study, we investigated how ESCRT-III dysfunction affects intracellular protein clearance using multiple genetic manipulations, including a dominant-negative form of VPS4 and an FTLD-associated CHMP2B mutant. We found that despite marked suppression of macroautophagic flux, inhibition of ESCRT-III promoted protein clearance in multiple cell types, including Neuro2a cells. Such clearance was also observed in ATG13-or ATG5-knockout cells, confirming that this process occurs independently of macroautophagy. Imaging revealed increased punctate accumulation of substrate proteins in lysosomes, suggesting the activation of a microautophagy-like pathway independent of ESCRT-III. In addition, ESCRT-III inhibition enhances extracellular vesicle-independent protein secretion. Cell-to-cell transmission of aggregated tau, assessed using conditioned medium, was also promoted by ESCRT-III inhibition. These findings suggested that ESCRT-III dysfunction, while impairing canonical autophagy, paradoxically activates alternative degradation and secretion pathways that may contribute to the pathogenesis of neurological disorders.

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Inhibition of ESCRT-III activates alternative pathways for protein degradation and secretion

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