Recent advances in understanding the role of proteostasis

Abstract

Maintenance of a functional proteome is achieved through the mechanism of proteostasis that involves precise coordination between molecular machineries assisting a protein from its conception to demise. Although each organelle within a cell has its own set of proteostasis machinery, inter-organellar communication and cell non-autonomous signaling bring forth the multidimensional nature of the proteostasis network. Exposure to extrinsic and intrinsic stressors can challenge the proteostasis network, leading to the accumulation of aberrant proteins or a decline in the proteostasis components, as seen during aging and in several diseases. Here, we summarize recent advances in understanding the role of proteostasis and its regulation in aging and disease, including monogenetic and infectious diseases. We highlight some of the emerging as well as unresolved questions in proteostasis that need to be addressed to overcome pathologies associated with damaged proteins and to promote healthy aging.

Keywords: Proteostasis; Unfolded Protein Response; aging; autophagy; metabolism; molecular chaperones; neurodegeneration; protein degradation; protein folding.

Figure 1.. Components of proteostasis helping in protein folding.

From its conception on the ribosome, a protein molecule folds to its native functional state with the help of two major proteostasis components. The left panel shows some of the representative components of a chaperone-based protein folding arm. In the right panel, we show metabolite-assisted folding of a protein. The folding landscape of a protein has been shown in the presence of three metabolites A, B, and C. On the extreme right, possible molecular mechanisms of metabolite-based protein folding are depicted. Gray represents solvent and green represents metabolite. CLIPS, chaperones linked to protein synthesis; HSP, heat shock protein.

Figure 2.. Problems in proteostasis and regulation of proteostasis.

The left side of the cell shows the molecular origins of problems in protein folding. Errors at various steps in the life cycle of a protein leading to protein degradation and protein aggregation, resulting in imbalance of proteostasis. On the right, a few of the different organelle-specific cellular responses to the imbalance of proteostasis are shown. They include inter-organelle and inter-cellular responses. Cyto-UPR, cytosolic unfolded protein response; DRiP, defective ribosomal product; ERAD, endoplasmic reticulum–associated degradation; GRAD, Golgi apparatus–related degradation; Mito-UPR, mitochondrial unfolded protein response; UPRam, unfolded protein response activated by mistargeting of proteins; UPR^ER, endoplasmic reticulum–associated unfolded protein response.

Figure 3.. Association between hallmarks of aging and collapse of proteostasis.

Despite decades-long research, it is still difficult to pinpoint to a definite cause-and-effect relationship between hallmarks of aging and collapse of proteostasis. On the left, a few important cellular hallmarks of aging are shown. On the right, age-associated global changes to proteostasis are shown. ERAD, endoplasmic reticulum–associated degradation; Mito-UPR, mitochondrial unfolded protein response.

Figure 4.. Proteostasis in diseases.

A summary of proteostasis-related diseases is presented. Many of the proteostasis-related diseases we know of have a genetic component. There has been considerable progress in deciphering the molecular mechanisms of many of these diseases. Still, a better understanding of eukaryotic stress-response pathways will take us a long way in the direction of treatment and cure.