Research over the last two decades has extended the paradigm of ATP- and ubiquitin-dependent proteasomal protein degradation by discovering that intrinsically unstructured proteins (IUPs) can be degraded by ubiquitin-independent alternative proteasomal pathways. Basic cellular processes appear to be regulated by various proteolytic systems acting on molecular switches in signal transduction. Ubiquitin proteasome system (UPS) and Ubiquitin-independent proteasomal protein degradation (UIPP) may crosstalk while competing for certain substrates. As central components of UIPP, 20S stand-alone proteasome, proteasome activator 28 (PA28) family proteins, and catalytic core regulators (CCR) may contribute to proteostasis or dysfunctional signal transduction in disease and aging.

As one of the brighter stars in the proteasome universe, anti-apoptotic proteasome activator 28 gamma (PA28γ; REGγ; encoded by the PSME3 gene) reveals multi-purpose perspectives for UPS-UIPP crosstalk. Due to its overexpression in solid cancers and its regulatory association with proteasomes, E3 ubiquitin protein ligases and chromatin, more focused research on this protein is required to unravel crosstalk mechanisms for a deeper understanding of cellular signaling in health, disease, and aging.

Recent advances in mass spectrometry opened qualitative and quantitative perspectives to estimate contributions of distinct proteolytic assemblies, demonstrating an amazing variability of proteolytic opportunities to let key regulatory proteins disappear from signal transduction pathways. Particularly under oxidative stress, the 20S proteasome dominates protein degradation, assisted by catalytic core regulators. However, other niches of regulated protein degradation involve nuclear regulators such as PA28γ, 20S proteasomes, and E3 ubiquitin ligases involved in chromatin modeling and DNA repair. How this proteolytic orchestra is playing, either with standard UPS instrumentation or with UIPP contribution, is still enigmatic.

Hence, this Research Topic should provide contributions describing new experimental techniques, findings, or concepts on regulatory compounds of 20S proteasomes and/or E3 enzymes interacting with their IUP substrates.

The aim of this Research Topic is to expand understanding of how dynamics and crosstalk between UPS and UIPP-mediated protein degradation in signal transduction are regulated by key elements such as PA28g or CCRs in association with proteasomes, E3 ligases, and substrates. The contributions should increase knowledge about the coordination of proteolytic systems in signal transduction with implications for aging and associated diseases.

We welcome findings particularly about:
• Degradation by the free 20S proteasome (without any of the regulators)
• Non-canonical (independent of proteasome activation) functions of PMSE3/PA28γ/REGγ
• Alterations of PA28γ functions due to disease-associated muteins
• Impact of PA28γ E3 ubiquitin ligase interaction in cell function
• PA28γ-modulated E3 function in UPS
• PA28γ-recruited new proteasome substrates in UIPP
• UIPP at the extracellular space
• GlcNac modification as a modulator of proteasomes/regulators/ substrate degradation

Implications related to disease or aging should focus on:
• Redox stress-related CCR roles
• Competition of CCR proteasome binding with other proteasome regulators
• UPS/UIPP crosstalk in apoptosis, DNA repair, and DNA damage response
• UPS/UIPP crosstalk in muscle tissue

We accept different article types including Mini-Reviews, Brief Research Reports and Perspectives. A full list of accepted article types, including descriptions, can be found at this link.

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Frontiers in Cell and Developmental Biology

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