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| Title | Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways. |
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| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 121, Issue 50, Page e2417390121, Year 2024 |
| Publish date | Dec 10, 2024 |
 Authors | Kelsey L Hickey / Alexandra Panov / Enya Miguel Whelan / Tillman Schäfer / Arda Mizrak / Ron R Kopito / Wolfgang Baumeister / Rubén Fernández-Busnadiego / J Wade Harper /   |
| PubMed Abstract | A hallmark of neurodegenerative diseases (NDs) is the progressive loss of proteostasis, leading to the accumulation of misfolded proteins or protein aggregates, with subsequent cytotoxicity. To ...A hallmark of neurodegenerative diseases (NDs) is the progressive loss of proteostasis, leading to the accumulation of misfolded proteins or protein aggregates, with subsequent cytotoxicity. To combat this toxicity, cells have evolved degradation pathways (ubiquitin-proteasome system and autophagy) that detect and degrade misfolded proteins. However, studying the underlying cellular pathways and mechanisms has remained a challenge, as formation of many types of protein aggregates is asynchronous, with individual cells displaying distinct kinetics, thereby hindering rigorous time-course studies. Here, we merge a kinetically tractable and synchronous agDD-GFP system for aggregate formation with targeted gene knockdowns, to uncover degradation mechanisms used in response to acute aggregate formation. We find that agDD-GFP forms amorphous aggregates by cryo-electron tomography at both early and late stages of aggregate formation. Aggregate turnover occurs in a proteasome-dependent mechanism in a manner that is dictated by cellular aggregate burden, with no evidence of the involvement of autophagy. Lower levels of misfolded agDD-GFP, enriched in oligomers, utilizes UBE3C-dependent proteasomal degradation in a pathway that is independent of RPN13 ubiquitylation by UBE3C. Higher aggregate burden activates the NRF1 transcription factor to increase proteasome subunit transcription and subsequent degradation capacity of cells. Loss or gain of NRF1 function alters the turnover of agDD-GFP under conditions of high aggregate burden. Together, these results define the role of UBE3C in degradation of this class of misfolded aggregation-prone proteins and reveals a role for NRF1 in proteostasis control in response to widespread protein aggregation. |
 External links | Proc Natl Acad Sci U S A / PubMed:39636856 / PubMed Central |
| Methods | EM (tomography) |
| Structure data |  EMDB-51460: Tomogram of aggregate in AgDD-sfGFP-expressing HEK293 cell 6 h post aggregation induction  EMDB-51461: Tomogram of aggregate in AgDD-sfGFP-expressing HEK293 cell 10 min post aggregation induction |
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Homo sapiens (human)