Replicative aging impedes stress-induced assembly of a key human protein disaggregase

Item Type:	Preprint
Title:	Replicative aging impedes stress-induced assembly of a key human protein disaggregase
Creators Name:	Mathangasinghe, Y. and Alberts, N. and Rosado, C.J. and Cox, D. and Payne, N.L. and Ormsby, A.R. and Alp, K.M. and Sakson, R. and Uthishtran, S. and Ruppert, T. and Arumugam, S. and Hatters, D.M. and Kampinga, H.H. and Nillegoda, N.B.
Abstract:	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 regulated in vivo remained 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.
Keywords:	Protein Disaggregation, Cellular Aging, Senescence, Heat Shock, Hsp70, J-Domain Proteins, VCP, Amyloid
Source:	bioRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	2022.06.25.497591
Date:	8 January 2023
Official Publication:	https://doi.org/10.1101/2022.06.25.497591

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