Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways DOI Creative Commons
Kelsey Hickey,

Alexandra Panov,

Enya Miguel Whelan

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(50)

Опубликована: Дек. 5, 2024

A hallmark of neurodegenerative diseases (NDs) is the progressive loss proteostasis, leading to accumulation misfolded proteins or protein aggregates, with subsequent cytotoxicity. To combat this toxicity, cells have evolved degradation pathways (ubiquitin–proteasome system and autophagy) that detect degrade proteins. However, studying underlying cellular mechanisms has remained a challenge, as formation many types aggregates asynchronous, individual displaying distinct kinetics, thereby hindering rigorous time-course studies. Here, we merge kinetically tractable synchronous agDD-GFP for aggregate targeted gene knockdowns, uncover used in response acute formation. We find forms amorphous by cryo-electron tomography at both early late stages Aggregate turnover occurs proteasome-dependent mechanism manner dictated burden, no evidence involvement autophagy. Lower levels agDD-GFP, enriched oligomers, utilizes UBE3C-dependent proteasomal pathway independent RPN13 ubiquitylation UBE3C. Higher burden activates NRF1 transcription factor increase proteasome subunit capacity cells. Loss gain function alters under conditions high burden. Together, these results define role UBE3C class aggregation-prone reveals proteostasis control widespread aggregation.

Язык: Английский

Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways DOI Creative Commons
Kelsey Hickey,

Alexandra Panov,

Enya Miguel Whelan

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(50)

Опубликована: Дек. 5, 2024

A hallmark of neurodegenerative diseases (NDs) is the progressive loss proteostasis, leading to accumulation misfolded proteins or protein aggregates, with subsequent cytotoxicity. To combat this toxicity, cells have evolved degradation pathways (ubiquitin–proteasome system and autophagy) that detect degrade proteins. However, studying underlying cellular mechanisms has remained a challenge, as formation many types aggregates asynchronous, individual displaying distinct kinetics, thereby hindering rigorous time-course studies. Here, we merge kinetically tractable synchronous agDD-GFP for aggregate targeted gene knockdowns, uncover used in response acute formation. We find forms amorphous by cryo-electron tomography at both early late stages Aggregate turnover occurs proteasome-dependent mechanism manner dictated burden, no evidence involvement autophagy. Lower levels agDD-GFP, enriched oligomers, utilizes UBE3C-dependent proteasomal pathway independent RPN13 ubiquitylation UBE3C. Higher burden activates NRF1 transcription factor increase proteasome subunit capacity cells. Loss gain function alters under conditions high burden. Together, these results define role UBE3C class aggregation-prone reveals proteostasis control widespread aggregation.

Язык: Английский

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