Protein quality control articles from across Nature Portfolio

Ge, Zhou, Fu et al. find caspase-2 accumulates in biomolecular condensates with ubiquitin and proteasomal components and functions as a deubiquitinase following stress. Caspase-2-deficient mice accumulate poly-ubiquitinated TDP-43 and show motor defects.

At the Golgi, the Dsc ubiquitin ligase complex targets proteins with shorter transmembrane domains for proteasomal or lysosomal degradation. This quality control at the sorting center of cells restricts the uncontrolled spreading of orphaned proteins.

This study highlights S-nitrosylation of p39, a post-translational modification in which nitric oxide is attached to free cysteine residues, as a novel aberrant redox protein modification involved in the synaptic dysfunction in Alzheimer’s disease pathogenesis.

ER quality control is crucial to maintain cellular homeostasis. Here, the authors identify a cytosolic ER-phagy regulator inducing ER fragmentation and ER-phagy that functions with an ER-resident receptor, finding a collaboration between cytosolic and ER-resident proteins in quality control.

The quality control of muscle myosin relies on the chaperone UNC-45. The chaperone binds folded and misfolded myosin and channel them into folding and degradation pathways. Interaction with UNC-45 is mediated by a conserved FX₃HY motif, carrying myopathy mutations that can cause myosin to aggregate.

The details of how the protein folding and degradation systems collaborate to combat potentially toxic non-native proteins are unknown. Here the authors perform systematic studies of missense and nonsense variants of the cytosolic aspartoacylase, ASPA, where loss-of-function variants are linked to Canavan disease.

Many proteins in the mouse ovary are extremely stable; they enhance proteostasis and limit protein aggregation, thereby supporting the maintenance of the long-lived oocytes.