Abstract
All eukaryotes rely on selective proteolysis to control the abundance of key regulatory proteins and maintain a healthy and properly functioning proteome. Most of this turnover is catalyzed by the 26S proteasome, an intricate, multi-subunit proteolytic machine. Proteasomes recognize and degrade proteins first marked with one or more chains of poly-ubiquitin, the addition of which is actuated by hundreds of ligases that individually identify appropriate substrates for ubiquitylation. Subsequent proteasomal digestion is essential and influences a myriad of cellular processes in species as diverse as plants, fungi and humans. Importantly, dysfunction of 26S proteasomes is associated with numerous human pathologies and profoundly impacts crop performance, thus making an understanding of proteasome dynamics critically relevant to almost all facets of human health and nutrition. Given this widespread significance, it is not surprising that sophisticated mechanisms have evolved to tightly regulate 26S proteasome assembly, abundance and activity in response to demand, organismal development and stress. These include controls on transcription and chaperone-mediated assembly, influences on proteasome localization and activity by an assortment of binding proteins and post-translational modifications, and ultimately the removal of excess or damaged particles via autophagy. Intriguingly, the autophagic clearance of damaged 26S proteasomes first involves their modification with ubiquitin, thus connecting ubiquitylation and autophagy as key regulatory events in proteasome quality control. This turnover is also influenced by two distinct biomolecular condensates that coalesce in the cytoplasm, one attracting damaged proteasomes for autophagy, and the other reversibly storing proteasomes during carbon starvation to protect them from autophagic clearance. In this review, we describe the current state of knowledge regarding the dynamic regulation of 26S proteasomes at all stages of their life cycle, illustrating how protein degradation through this proteolytic machine is tightly controlled to ensure optimal growth, development and longevity.
Highlights
Specialty section: This article was submitted to Protein Folding, Misfolding and Degradation, a section of the journal Frontiers in Molecular Biosciences
We describe the current state of knowledge regarding the dynamic regulation of 26S proteasomes at all stages of their life cycle, illustrating how protein degradation through this proteolytic machine is tightly controlled to ensure optimal growth, development and longevity
This includes intricate knowledge of the 26S proteasome itself, which combines strict substrate selectivity with extreme promiscuity with respect to substrate processing to enable the degradation of thousands of proteins with exquisite specificity
Summary
All cellular organisms require mechanisms to purge unwanted or dysfunctional proteins. Precise selectively is dictated by a suite of receptors that tether appropriate substrates to the enveloping autophagic membranes (Rogov et al, 2014; Khaminets et al, 2016; Gatica et al, 2018). Perhaps unsurprisingly given their widespread influence, definitive etiological links exist between various human diseases and mutations in genes that control the UPS and autophagic degradation routes. Knowledge of how the UPS, 26S proteasomes and autophagy are regulated, and of how these systems overlap to ensure proteostasis, is of considerable importance
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