Regulation of the 20S Proteasome by a Novel Family of Inhibitory Proteins

Abstract

Aims: The protein degradation machinery plays a critical role in the maintenance of cellular homeostasis, preventing the accumulation of damaged or misfolded proteins and controlling the levels of regulatory proteins. The 20S proteasome degradation machinery, which predominates during oxidative stress, is able to cleave any protein with a partially unfolded region, however, uncontrolled degradation of the myriad of potential substrates is improbable. This study aimed to identify and characterize the regulatory mechanism that controls 20S proteasome-mediated degradation. Results: Using a bioinformatic screen based on known 20S proteasome regulators, we have discovered a novel family of 20S proteasome regulators, named catalytic core regulators (CCRs). These regulators share structural and sequence similarities, and coordinate the function of the 20S proteasome by affecting the degradation of substrates. The CCRs are involved in the oxidative stress response via Nrf2, organizing into a feed-forward loop regulatory circuit, with some members stabilizing Nrf2, others being induced by Nrf2, and all of them inhibiting the 20S proteasome. Innovation and Conclusion: These data uncover a new family of regulatory proteins that utilize a fine-tuned mechanism to carefully modulate the activity of the 20S proteasome, in particular under conditions of oxidative stress, ensuring its proper functioning by controlling the degradative flux. Antioxid. Redox Signal. 32, 636-655.

Conformational maps of human 20S proteasomes reveal PA28- and immuno-dependent inter-ring crosstalks

“…The same is true for the many PIPs that regulate proteasome function and are still poorly characterized from a structural point of view 53 . More broadly, this work demonstrates the ability of HDX-MS to investigate dynamic events on megadalton assemblies including ribosomal particles, inflammasomes and nucleosomes, to name a few.…”

Somatostatin Interneurons of the Insula Mediate QR2-Dependent Novel Taste Memory Enhancement

“…This second phase of molecular mechanisms underlying memory consolidation may result in different protein synthesis, depending on cell type, and may cause either QR2 activity or protein-protein interaction mediated shifts that are unique to SST interneurons. Indeed, this may equally be true for excitatory cells, where the slight decrease in QR2 observed may augment or affect longer term aspects of cell function, possibly via proteostasis (Olshina et al, 2020) for example, to stabilize the memory trace over longer time periods, differently from, but along with, SST interneurons.…”

“…We expect other targets besides Kv2.1 to be identified in the future, and these may be cell type specific in their expression pattern, similarly to QR2 and eIF2 . Certainly, how SST interneurons are affected by QR2 redox and via which channel or cellular component, or indeed whether QR2 pathway activation causes other, non-redox mediated changes, are additional issues that requires future efforts to decipher (Olshina et al, 2020;Sonavane et al, 2020;Hayat et al, 2021). Ultimately, how this altered SST interneuron activity subsequently affects the neuronal circuit/s involved in novel taste memory formation poses a substantial and important task for future research.…”

“…Recently, we described a central pathway downstream of ACh in the aIC that is necessary for novel taste memory formation, in which QR2 acts as a removable constraint, in parallel and possibly separately from proteostasis (Rappaport et al, 2015;Gould et al, 2020b). Though reduced QR2 expression may affect the cell in a number of ways (Olshina et al, 2020;Sonavane et al, 2020), we identified that by removing QR2, which continuously generates physiological levels of reactive oxygen species (ROS), the aIC becomes less oxidized. Thus, levels of oxidized and deactivated voltage gated potassium channel Kv2.1 are reduced, hours following learning, presumably along with other redox sensitive cellular components.…”

Concept and application of circulating proteasomes

“…However, a growing number of endogenous substrates of the 20S proteasome with diverse physiological functions have been identified over the last decade, and now, this ubiquitin- and ATP-independent mode of proteasomal degradation is generally perceived as an alternative key regulator of the cellular proteome. Notably, the 20S proteasome degrades either fully or partially disordered proteins, including amyloid-β peptides 9 , tau 10 , 11 , α-synuclein 12 , 13 , and the cell-cycle-regulating proteins p21, p53, and p73 14 – 16 . In addition, oxidatively modified proteins, which largely affect the intracellular signaling pathway and cell viability when they accumulate, also form a class of 20S substrates 17 , 18 .…”