Excess linear ubiquitination disrupts aggregate clearance and impairs proteostasis in cells

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.