A proteotoxic stress response specific to exhausted T cells, governed by AKT signaling and accompanied by increased protein translation, represents a mechanistic vulnerability and a new therapeutic target to improve cancer immunotherapies.

Langin et al. find that ER-associated sorting (ERAS) directs NAC53/78 turnover and activation to couple proteasome induction with repression of photosynthesis genes, linking proteostasis to energy met...

Langin et al. find that ER-associated sorting (ERAS) directs NAC53/78 turnover and activation to couple proteasome induction with repression of photosynthesis genes, linking proteostasis to energy metabolism during stress.

imageimageADP-ribosylation is thought to occur on specific sites to affect specific characteristics of target proteins. Here, it is found to play a more promiscuous role, with PARP7 labelling proteins for efficient degradation during proteotoxic ...

A proteotoxic stress response specific to exhausted T cells, governed by AKT signaling and accompanied by increased protein translation, represents a mechanistic vulnerability and a new therapeutic ta...

Langin et al. find that ER-associated sorting (ERAS) directs NAC53/78 turnover and activation to couple proteasome induction with repression of photosynthesis genes, linking proteostasis to energy metabolism during stress.

Lu et al. show that, under proteotoxic stress, TDP-43 inclusions of skein-like morphology are guided by the chaperone HSP70 and its nucleotide exchange factor BAG3 to induce TDP-43 co-aggregation with...

When under stress, plants cut back on energy production to focus on breaking down damaged proteins.

Neurodegenerative diseases are frequently associated with proteotoxic stress linked to disease specific proteins. The autophagy-lysosome system provides essential control of proteotoxic stress and its failure can lead to initiation of apoptosis. However, in aging and neurodegenerative diseases apoptosis is insufficient to account for all neuronal death, and several different cell death types have been reported in these contexts. Here we show that karyoptosis, a distinct form of cell death, can be induced by proteotoxic stress and then develops through nuclear degeneration and cellular expulsion of nuclear material. We establish that karyoptosis is regulated by the p38 kinase signalling pathway, which controls stability of the nuclear lamina protein LaminB1 via direct phosphorylation. We demonstrate that karyoptosis affects neurons in models of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) pathology. Finally, we identify karyoptotic features in post-mortem frontal cort

Touvier et al. investigate the role of the UPR transcription factor XBP1s in models of proteotoxic Charcot-Marie-Tooth type 1B. They show that activation o

Proteotoxic stress, characterized by the accumulation of damaged proteins, poses a significant challenge to cellular homeostasis. To mitigate proteotoxicity euk

High-resolution spatial proteomics were used to map molecular events during hepatocyte stress in pseudotime across all fibrosis stages, recapitulating known disease progression markers and revealing e...