Excess linear ubiquitination disrupts aggregate clearance and impairs proteostasis in cells
Inactivating the ligase HOIL-1 solidifies dynamic protein condensates and impairs the autophagic clearance of tau, amyloid-beta, and alpha-synuclein aggregates.
The EMBO journal · Kaypee S et al. · Paper published 28 Sep 2026
In cell models, researchers investigated how the ubiquitin ligase HOIL-1 regulates Met1-linked ubiquitination to control aggregate clearance. Cells expressing catalytically inactive HOIL-1 accumulated higher levels of amyloid-beta, tau, and alpha-synuclein aggregates. This defect stemmed from impaired late-stage autophagic flux, where the transport of p62-positive aggregates to lysosomes was blocked. In parallel, dynamic liquid-like p62 condensates shifted into rigid, solid-like structures. Elevating Met1-linked ubiquitin chains by either HOIL-1 inactivation or by depleting the deubiquitinase OTULIN produced identical defects. These findings demonstrate that HOIL-1 maintains cellular proteostasis and enables aggregate degradation by precisely limiting Met1-linked ubiquitination.
Why it matters
Loss of proteostasis and the buildup of toxic protein aggregates are central hallmarks of aging and age-related neurodegenerative diseases.
Caveats
The findings are limited to cell culture experiments, and the mechanisms have not yet been evaluated in intact animal models or human tissues.
Written from the paper’s abstract, and every claim checked against it before publishing. Read the paper for the full methods and data.
The paper
Excess Met1-linked ubiquitination leads to solid aggregate formation
Kaypee S, Miyasaka M, Nakajima T et al.
The EMBO journal · 28 Sep 2026 · Peer-reviewed
- Relevance
- Relevant
- News value
- Notable
- Evidence
- Cells
- Status
- Peer-reviewed
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