| Autor: |
Yasith Mathangasinghe, Niels Alberts, Carlos J. Rosado, Dezerae Cox, Natalie L. Payne, Angelique R. Ormsby, Keziban Merve Alp, Roman Sakson, Sanjeev Uthishtran, Thomas Ruppert, Senthil Arumugam, Danny M. Hatters, Harm H. Kampinga, Nadinath B. Nillegoda |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.06.25.497591 |
| Popis: |
The collapse of protein homeostasis manifests itself in a toxic protein aggregation cascade, which is associated with degenerative diseases and aging. To solubilize aggregates, dedicated protein disaggregases exist in unicellular organisms, but these have no nuclear/cytosolic orthologs in metazoa. Alternative metazoan disaggregation machines have been described, but how these are operated and regulatedin vivoremained unknown. We show that protein disaggregases are functionally diversified in human cells to efficiently target different types of stress-induced aggregates in sequential and temporally distinct phases. In particular, we show the selective assembly of an Hsp70-DNAJA1-DNAJB1 trimeric disaggregase that forms during late phase of stress recovery.,i.e., after VCP-dependent solubilization of non-native proteins that accumulate in cellular condensates such as nucleoli or stress granules. When activated, the trimeric disaggregase provides resistance to stress toxicity and contributes to amyloid disposal. Strikingly, this disaggregase collapses early in cells undergoing replicative aging with important underlining pathophysiological consequences. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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